Monia Garofolo

Clinical worthlessness of genetic prediction of common forms of diabetes mellitus and related chronic complications: A position statement of the Italian Society of Diabetology

AIM We are currently facing several attempts aimed at marketing genetic data for predicting multifactorial diseases, among which diabetes mellitus is one of the more prevalent. The present document primarily aims at providing to practicing physicians a summary of available data regarding the role of genetic information in predicting diabetes and its chronic complications. DATA SYNTHESIS Firstly, general information about characteristics and performance of risk prediction tools will be presented in order to help clinicians to get acquainted with basic methodological information related to the subject at issue. Then, as far as type 1 diabetes is concerned, available data indicate that genetic information and counseling may be useful only in families with many affected individuals. However, since no disease prevention is possible, the utility of predicting this form of diabetes is at question. In the case of type 2 diabetes, available data really question the utility of adding genetic information on top of well performing, easy available and inexpensive non-genetic markers. Finally, the possibility of using the few available genetic data on diabetic complications for improving our ability to predict them will also be presented and discussed. For cardiovascular complication, the addition of genetic information to models based on clinical features does not translate in a substantial improvement in risk discrimination. For all other diabetic complications genetic information are currently very poor and cannot, therefore, be used for improving risk stratification. CONCLUSIONS In all, nowadays the use of genetic testing for predicting diabetes and its chronic complications is definitively of little value in clinical practice.

A Fermented Whole Grain Prevents Lipopolysaccharides-Induced Dysfunction in Human Endothelial Progenitor Cells

Endogenous and exogenous signals derived by the gut microbiota such as lipopolysaccharides (LPS) orchestrate inflammatory responses contributing to development of the endothelial dysfunction associated with atherosclerosis in obesity, metabolic syndrome, and diabetes. Endothelial progenitor cells (EPCs), bone marrow derived stem cells, promote recovery of damaged endothelium playing a pivotal role in cardiovascular repair. Since healthy nutrition improves EPCs functions, we evaluated the effect of a fermented grain, Lisosan G (LG), on early EPCs exposed to LPS. The potential protective effect of LG against LPS-induced alterations was evaluated as cell viability, adhesiveness, ROS production, gene expression, and NF-kB signaling pathway activation. Our results showed that LPS treatment did not affect EPCs viability and adhesiveness but induced endothelial alterations via activation of NF-kB signaling. LG protects EPCs from inflammation as well as from LPS-induced oxidative and endoplasmic reticulum (ER) stress reducing ROS levels, downregulating proinflammatory and proapoptotic factors, and strengthening antioxidant defense. Moreover, LG pretreatment prevented NF-kB translocation from the cytoplasm into the nucleus caused by LPS exposure. In human EPCs, LPS increases ROS and upregulates proinflammatory tone, proapoptotic factors, and antioxidants. LG protects EPCs exposed to LPS reducing ROS, downregulating proinflammatory and proapoptotic factors, and strengthening antioxidant defenses possibly by inhibiting NF-κB nuclear translocation.

The rs12917707 polymorphism at the UMOD locus and glomerular filtration rate in individuals with type 2 diabetes: Evidence of heterogeneity across two different European populations

Background UMOD variability has been associated at a genome-wide level of statistical significance with glomerular filtration rate (GFR) in Swedish individuals with type 2 diabetes (T2D; n = 4888). Whether this finding is extensible also to diabetic patients from other populations deserves further study. Our aim was to investigate the relationship between UMOD variability and GFR in patients with T2D from Italy. Methods Genotyping of the single nucleotide polymorphism (SNP) rs12917707 at the UMOD locus has been carried out in 3087 individuals from four independent Italian cohorts of patients with T2D by TaqMan allele discrimination. Results In none of the four study cohorts was rs12917707 significantly associated with GFR (P > 0.05 for all). Similar results were obtained when the four samples were pooled and analyzed together (β = 0.83, P = 0.19). Such effect was strikingly smaller than that previously reported in Swedish patients (P for heterogeneity = 1.21 × 10-7). Conclusions The previously reported strong association between rs12917707 and GFR in diabetic patients from Sweden is not observed in Italian diabetic patients, thus clearly pointing to a heterogeneous effect across the two different samples. This suggests that UMOD is a strong genetic determinant of kidney function in patients with T2D in some, but not all, populations.

Pharmacogenetics of oral antidiabetes drugs: evidence for diverse signals at the IRS1 locus

To investigate the role of IRS1 locus on failure to oral antidiabetes drugs (OADs) we genotyped single-nucleotide polymorphisms (SNPs), rs2943641, rs7578326 (tagging all SNPs genome-wide associated with type 2 diabetes (T2D) and related traits at this locus) and rs1801278 (that is, the loss-of-function IRS1 G972R amino acid substitution) in 2662 patients with T2D. Although no association with OAD failure was observed for rs2943641 and rs7578326 SNPs (odds ratio (OR): 1.04, 95% confidence interval (CI): 0.93–1.16 and OR: 0.97, 95% CI: 0.87–1.09 respectively), a significant association was observed for rs1801278 (OR: 1.34, 95% CI: 1.08–1.66). When meta-analyzed with previous published data, an allelic OR of 1.41 (1.15–1.72; P=0.001) was obtained, so that homozygous R972R individuals have >80% higher risk of failing to OADs as compared with their G972G counterparts. In all, though further studies are needed for confirming this finding, our present data point to IRS1 rs1801278 as a potential biomarker for pursuing the goal of stratified medicine in the field of antihyperglycemic treatment in T2D.

Albuminuric and non-albuminuric chronic kidney disease in type 1 diabetes: Association with major vascular outcomes risk and all-cause mortality

AIMS Albuminuric and non-albuminuric phenotypes of chronic kidney disease (CKD) may have different cardiovascular risk and survival in type 1 diabetes (T1DM). Herein we estimated risk of major vascular outcomes by the EURODIAB PCS score and determined all-cause mortality rate in 774 T1DM according to CKD phenotypes. METHODS We evaluated the distribution of CKD phenotypes [no CKD, stages 1-2, non-albuminuric stage ≥3 (Alb-CKD), albuminuric stage ≥3 (Alb+CKD)], the EURODIAB risk score for major vascular outcomes [low- (LS), intermediate- (IS), and high- (HS) risk] and all-cause mortality over a follow-up of 8.25 ± 2.34 years. RESULTS Out of 774 subjects, 692 (89.4%) had no CKD, 53 (6.8%) CKD stages 1-2, 17 (2.2%) Alb-CKD and 12 (1.6%) Alb+CKD; 466 (60.2%) had LS, 205 (26.5%) IS and 103 (13.3%) HS. Distribution of HS was: no CKD, 9.1%; CKD stages 1-2, 34.0%; Alb-CKD, 64.7%; Alb+CKD, 91.7% (P < 0.0001). Mortality increased from no CKD, 3.0%; to stages 1-2, 15.1% (HR 4.504); Alb-CKD, 29.4% (8.573); Alb+CKD, 50.0% (20.683, P < 0.0001). Accounting for age and sex, HRs for mortality compared to no CKD were: CKD stages 1-2, 3.84 (P = 0.001); Alb-CKD, 2.97 (P = 0.046); Alb+CKD, 7.44 (P < 0.0001). Adjusting for sex and the EURODIAB score, HRs for mortality compared to no CKD were: CKD stages 1-2, 2.57 (P = 0.027); Alb-CKD, 2.77 (P = 0.058); Alb+CKD, 4.58 (P = 0.003). CONCLUSIONS In our T1DM cohort, one fifth of those with CKDs were non-albuminuric. This phenotype was associated with higher risk of major outcomes and similar rate of mortality as compared to CKD stages 1-2. The greatest risk and highest mortality occur in patients with Alb+CKD.

Microvascular Disease Burden and All-Cause Mortality in Type 1 Diabetes-A 10-Year Follow-Up Study

Type 1 diabetes (T1D) is associated with a sustantially increased risk of cardiovascular (CV) events and premature death. The effect of the microvascular disease (MD) burden, i.e., the cumulative burden of retinopathy, nephropathy and peripheral neuropathy on all-cause mortality was evaluated in 774 T1D (age 40.2±11.7; DD 19.4±12.2 years; HbA1c 7.8±1.2%) in a mean follow-up of 10.6±2.5 years. Distribution of MD was: no-MD: n. 425 (54.9%); MD1: 250 (32.3%); MD2: 75 (9.7%); MD3: 24 (3.1%). Distribution was unchanged after esclusion of 41 T1D (5.3%) with previous CV events (CV+; 57.0%, 32.2%, 8.5% and 2.3%, respectively). Compared to no-MD, MD1-3 groups showed an adverse CV risk profile with steeply increase in age, DD, BMI, WHR, BP, HbA1c, uric acid and EURODIAB PCS risk score for major vascular outcomes (p Disclosure M. Garofolo: None. R. Giannarelli: None. M. Aragona: None. D. Lucchesi: None. L. Giusti: None. V. Sancho-Bornez: None. G. Daniele: None. R. Miccoli: None. G. Penno: None. S. Del Prato: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, GlaxoSmithKline plc., Intarcia Therapeutics, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Servier, Sanofi, Takeda Pharmaceuticals U.S.A., Inc.. Research Support; Self; Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca. Speaker9s Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Takeda Pharmaceuticals U.S.A., Inc.. Advisory Panel; Self; Janssen Biotech, Inc., Abbott.

Normoalbuminuric chronic kidney disease in type 1 diabetes: is it real and is it serious? Reply to Rigalleau V, Blanco L, Alexandre L et al [letter]

To the Editor: We really appreciated the interest and comments by Rigalleau and colleagues on our recent article [1]. We agree that the proportion of individuals with the nonalbuminuric (Alb) phenotype with type 1 diabetes and chronic kidney disease (CKD) in our study was surprisingly high (17 out of 29, 58.6%) [2]. This figure is higher than that reported by Thorn et al [3] in the FinnDiane Study (78 out of 502, 15.5%; p < 0.0001, χ test) and, also, in the DCCT/Epidemiology of Diabetes Interventions and Complications (EDIC) Study [4], in which 23.6% of individuals (21 out of 89; p < 0.001, χ test) were reported as having normoalbuminuria (albumin excretion rate [AER] ≤ 30 mg/ 24 h) and estimated GFR (eGFR) < 60 ml min [1.73 m]. Nonetheless, our figure is similar to the one reported in the Renal Insufficiency And Cardiovascular Events (RIACE) Study [5], which enrolled a large cohort of Italian individuals with type 2 diabetes and found that 1673 out of 2959 (56.5%) individuals with eGFR < 60 ml min [1.73 m] had normoalbuminuria. The reasons for these discrepancies are not readily apparent. Whether local pathogenic background and clinical management could contribute to these differences is a hypothesis that needs to be verified. Rigalleau et al claim that our results may be overestimated by the assessment of glomerular filtration rate by the Modification of Diet in Renal Disease (MDRD) Study equation. Though we are fully aware of the limitations of this equation, this is unlikely to account for the observed discrepancies as the same approach was used in the DCCT/EDIC survey [4]. Moreover, as reported in the supplementary material of our study (ESMTable 5 [2]), individuals with CKD and the Alb phenotype had higher MDRD equation-eGFR vs those with the albuminuric (Alb) phenotype (52 ± 7 vs 45 ± 11 ml min [1.73 m] ; p < 0.05). This difference was probably even larger in the FinnDiane [3] study, in which participants with CKD and the Albphenotype had a median (interquartile range) eGFR, calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula [6], of 55 (49–58), whilst those with the Alb phenotype had an eGFR of 37 (23–51) ml min [1.73 m]. Furthermore, a less * Giuseppe Penno pgiuse@immr.med.unipi.it