GENETIC DETERMINANTS OF TYPE 2 DIABETES AND ASSOCIATED CARDIOMETABOLIC DISORDERS / DETERMINANTI GENETICI DI DIABETE MELLITO DI TIPO 2 E FENOTIPI CARDIOMETABOLICI ASSOCIATI

Il presente progetto di ricerca si compone di tre parti: (1) revisione della letteratura relativa ai determinanti genetici di diabete mellito tipo 2, malattie coronariche e fenotipi intermedi (forme sub-diabetiche di iperglicemia, forme subcliniche di aterosclerosi e fattori di rischio associati) alla ricerca di possibili aree di sovrapposizione; (2) verificare se i determinanti di rischio genetico per diabete tipo 2, ed in particolare quelli maggiormente associati a insulino-resistenza, sono anche associati a misure di aterosclerosi subclinica; (3) verificare se uno score di rischio genetico costituito dai determinanti genetici di diabete tipo 2, infarto miocardico, stroke, fibrillazione atriale, morte cardiaca improvvisa, malattie coronariche \ue8 associato a mortalit\ue0 per tutte le cause e/o mortalit\ue0 per malattie cardiovascolari. Il diabete mellito di tipo 2 (T2D) \ue8 una malattia complessa ad alta prevalenza e incidenza che riconosce fattori genetici e non-genetici quali determinanti causali. Le malattie cardiovascolari (CVD) sono una delle maggiori cause di morte e sono spesso associate a T2D. Studi di associazione genome-wide hanno identificato varianti genetiche comuni associate a T2D, CVD e fenotipi cardiometabolici intermedi. Questo percorso di ricerca si \ue8 proposto di individuare le basi genetiche comuni a T2D, CVD e forme sub-diabetiche di iperglicemia attraverso tre studi esemplificativi. Nel primo studio \ue8 stato verificato se il rischio genetico per T2D sia associato, in aggregato e/o in sottogruppi funzionali distinti (disfunzione beta-cellulare o insulino-resistenza), a tratti di aterosclerosi subclinica (ATS) in coorti multi-etniche. Il secondo studio ha testato l\u2019ipotesi che la variabilit\ue0 genetica comune dei loci principalmente coinvolti nella trasduzione del segnale insulinico siano associati a insulino-resistenza, funzione beta-cellulare, anomalie elettrocardiografiche e/o aterosclerosi subclinica in soggetti affetti da T2D neo-diagnosticato. Nel terzo studio \ue8 stato indagato se il rischio genetico per T2D e tratti di rischio cardiometabolico sia associato ad aumentata mortalit\ue0 nel Framingham Offspring Study. Il diabete mellito di tipo 2 (T2D) \ue8 una malattia complessa ad alta prevalenza e incidenza che riconosce fattori genetici e non-genetici quali determinanti causali. Le malattie cardiovascolari (CVD) sono una delle maggiori cause di morte e sono spesso associate a T2D. Studi di associazione genome-wide hanno identificato varianti genetiche comuni associate a T2D, CVD e fenotipi cardiometabolici intermedi. Il presente percorso di ricerca mira ad individuare le basi genetiche comuni a T2D, CVD e forme subdiabetiche di iperglicemia attraverso tre studi esemplificativi. Il primo studio si propone di verificare se il rischio genetico per T2D sia associato, in aggregato e/o in sottogruppi funzionali distinti (disfunzione beta-cellulare o insulino-resistenza), a tratti di aterosclerosi subclinica (ATS) in coorti multi-etniche; il secondo verifica l\u2019ipotesi che la variabilit\ue0 genetica comune dei loci principalmente coinvolti nella trasduzione del segnale insulinico siano associati a insulino-resistenza, funzione beta-cellulare, anomalie elettrocardiografiche e/o aterosclerosi subclinica in soggetti affetti da T2D neo-diagnosticato.; il terzo verifica l\u2019ipotesi se il rischio genetico per T2D e tratti di rischio cardiometabolico si associno ad aumentata mortalit\ue0 nello studio Framingham.T2D is a complex disease characterized by a high prevalence and incidence worldwide, and recognizes genetic and non-genetic (environmental) risk factors as underlying determinants. CVD are currently one of the leading causes of death and are also often clinically associated to T2D. Recent large-scale genome-wide association studies (GWAS) have identified common genetic risk variants associated with a higher propensity of developing T2D, CVD and intermediate cardiometabolic phenotypes. The goal of the research project herein presented was three-fold: (1) to critically revise the available literature about the genetic determinants of type 2 diabetes (T2D), coronary heart disease (CHD) and intermediate phenotypes (sub-diabetic hyperglycemia, measures of subclinical atherosclerosis (SCA) and associated risk conditions), aimed at searching for potential overlapping areas of shared genetic background; (2) to verify whether the genetic determinants of T2D, and particularly those associated with insulin resistance, are also associated with measures of SCA; (3) to verify whether a genetic risk score comprised of the genetic determinants of T2D, myocardial infarction, stroke, atrial fibrillation, sudden cardiac death, coronary heart disease, is associated with an excess risk of all-cause mortality and/or CVD death. In detail, the present research exercise aimed at exploring the common genetic background of T2D, CVD and sub-diabetic forms of hyperglycemia by means of three exemplifying studies herein outlined. The first study verified whether the genetic risk for T2D, as represented by the aggregate burden of T2D risk loci (either as a whole or by distinct functional sub-groups, representative of loci with prior evidence of association with defective beta-cell function and/or increased insulin resistance), is associated with SCA traits in multi-ethnic cohorts. The second study verified the hypothesis that the common genetic variability at loci gatekeepers of the insulin signaling transduction pathway are associated with insulin resistance, beta-cell dysfunction, pathologic electrocardiogram, and/or increased SCA in patients affect by newly-diagnosed T2D. The third study verified whether the composite of the genetic determinants of T2D and intermediate CVD risk traits is associated with a higher mortality in the Framingham Offspring Study

The power of numbers

The technical and methodological advancements, as well as the knowledge accrued over the past decade on the haplotype block structure of the human genome, have enabled investigators to tackle the complexity of the genetic architecture of type 2 diabetes in populations of European and non-European descent by performing large-scale genome-wide association studies (GWAS) for both common and rare genetic variants. Interestingly, while interpreting the GWAS results one may observe that as the number of identified type 2 diabetes risk variants has increased over time, and the loci uncovered by earlier GWAS have been further replicated in larger association studies, the individual (per-allele) effect estimate has become smaller than the one originally detected in the discovery GWAS. This may be due to the non-mutually exclusive occurrence of two statistical phenomena, usually dubbed as "winner's curse" and "spectrum bias" effects. The present commentary discusses the work of the China Kadoorie Biobank Collaborative Group, which sought to provide a demonstration of the calculation of (relatively) unbiased allelic effect sizes for a set of 56 established type 2 diabetes risk variants in a large population-based cohort study of Chinese adult individuals. In particular we critically discuss whether theGWAS approach should remain a matter of statistical constraints only, or whether its integration with functional maps may highlight some sub-threshold loci as informative as those that reach genome-wide significance. The complementary information that could arise from the full integration of the genetic and functional maps holds the promise of potentially uncovering clinically relevant mechanistic insights and might expand the regulatory framework in which to interpret the functional follow-up and fine-mapping currently ongoing at established type 2 diabetes risk loci

Probiotic Soy Milk: A Call to Action

In a recently published clinical trial, Ghiasvand R et al have shown that the 8-week consumption of 200 mL/day probiotic soy milk fortified with Lactobacillus plantarum A7 may exert favorable changes on biomarkers of oxidative stress in patients with type 2 diabetes and concomitant diabetic kidney disease (DKD)

SGLT1 and SGLT1 Inhibitors: A Role to Be Assessed in the Current Clinical Practice

Diabetes is a complex disease of increasingly common occurrence worldwide. Attaining optimal glycemic control is the main challenge to prevent the development of diabetes-related complications and/or to stop their progression. In recent years, the pharmacologic toolkit for the treatment of diabetes has considerably expanded, thus paving the way to more pathophysiology-oriented therapies. For instance, the sodium-glucose cotransporters SGLT2 and SGLT1 have been in the spotlight because of better knowledge of their physiology and therapeutic potential. At present, whereas the SGLT2 inhibitors are widely applied in current clinical practice as an effective and well-tolerated treatment that increases the urinary excretion of glucose, less is known about the use of SGLT1 inhibitors. SGLT1s are of primary importance in the small intestine, an organ that does not express SGLT2, while in the kidney they are expressed in the late renal proximal tubules, where it reabsorbs the glucose escaped from the upstream SGLT2. Hence, SGLT1-mediated glucose reabsorption in the kidney is increased when the tubular glucose load overwhelms the capacity of SGLT2 or when the latter is inhibited. The role of SGLT1 in intestinal and renal glucose transport makes the transporter a potential target for antidiabetic therapy. Here, we briefly report the evidence on LX2761, a new inhibitor against SGLT1 and SGLT2 in vitro, which acts in vivo as a selective inhibitor of SGLT1 in the gastrointestinal tract. LX2761 improves glycemic control without the glycosuria-related side effects of SGLT2 inhibitors, particularly genitourinary tract infections. However, whether it represents a valid therapeutic option for all patients with diabetes or is more appropriate for specific phenotypes, e.g., patients with concomitant diabetes and chronic kidney disease, who may benefit less from the renal mechanism of selective SGLT2 inhibitors, remains to be tested in large randomized controlled trials

Association of free-living physical activity measures with metabolic phenotypes in type 2 diabetes at the time of diagnosis. The Verona Newly Diagnosed Type 2 Diabetes Study (VNDS)

Objective: Lifestyle is considered a major determinant of risk of type 2 diabetes (T2D). We investigated whether daily physical activity (DPA) is associated with beta-cell function (BF) and/or insulin sensitivity (IS) in patients with T2D at the time of diagnosis. Methods: In 41 subjects enrolled in the Verona Newly-Diagnosed Type 2 Diabetes Study we assessed: (1) IS, by euglycaemic insulin clamp; (2) BF, estimated by prolonged-OGTT minimal modeling and expressed as derivative and proportional control; (3) DPA and energy expenditure (EE), assessed over 48-hours monitoring by a validated wearable armband system. Results: Study participants (median[IQR]; age: 62 [53-67] years, BMI: 30.8 [26.5-34.3] Kg c5m-2, HbA1c: 6.7 [6.3-7.3]%; 49.7 [45.4-56.3] mmol/mol) were moderately active (footsteps/day: 7,773 [5,748-10,927]; DPA 653MET: 70 [38-125] min/day), but none of them exercised above 6 metabolic equivalents (MET). EE, expressed as EETOT (total daily-EE) and EE 653MET (EE due to DPA 653MET) were 2,398 [2,226-2,801] and 364 [238-617] Kcal/day, respectively. IS (M-clamp 630 [371-878] \u3bcmol/min/m2) was positively associated with DPA and EE, independent of age, sex and BMI (p<0.05). Among the DPA and EE parameters assessed, DPA 653MET and EETOT were independent predictors of IS in multivariable regression analyses, adjusted for age, sex, BMI (R2=16%, R2=19%, respectively; p<0.01). None of model-derived components of BF was significantly associated with DPA or accompanying EE. Conclusions Our study highlighted moderate levels of DPA and total EE as potential determinants of IS, but not BF, in T2D at the time of diagnosis. Intervention studies are needed to conclusively elucidate the effect of DPA on these features

A Novel Insulin/Glucose Model after a Mixed-Meal Test in Patients with Type 1 Diabetes on Insulin Pump Therapy

Current closed-loop insulin delivery methods stem from sophisticated models of the glucose-insulin (G/I) system, mostly based on complex studies employing glucose tracer technology. We tested the performance of a new minimal model (GLUKINSLOOP 2.0) of the G/I system to characterize the glucose and insulin dynamics during multiple mixed meal tests (MMT) of different sizes in patients with type 1 diabetes (T1D) on insulin pump therapy (continuous subcutaneous insulin infusion, CSII). The GLUKINSLOOP 2.0 identified the G/I system, provided a close fit of the G/I time-courses and showed acceptable reproducibility of the G/I system parameters in repeated studies of identical and double-sized MMTs. This model can provide a fairly good and reproducible description of the G/I system in T1D patients on CSII, and it may be applied to create a bank of "virtual" patients. Our results might be relevant at improving the architecture of upcoming closed-loop CSII systems

Mortality from infectious diseases in diabetes

Background and Aims: to investigate the risk of mortality from infections by comparing the 33 underlying causes of death versus the multiple causes of death in known diabetic subjects living in 34 the Veneto Region, Northern Italy. 35 Methods and Results: 185,341 diabetic subjects aged 30-89 years were identified in the year 2010 36 and causes of death were assessed from 2010 to 2015. Standardized Mortality Ratios (SMR) with 37 95% confidence intervals were computed with regional mortality rates as reference. The underlying 38 causes of death and all the diseases reported in the death certificates were scrutinized. At the end of 39 the follow-up, 36,382 subjects had deceased. We observed an increased risk of death from 40 infection-related causes in subjects affected by diabetes with a SMR of 1.83 (95 % CI, 1.71-1.94). 41 The SMR for death from septicemia was 1.91 (95 % CI, 1.76-2.06) and from pneumonia 1.47 (95 % 42 CI, 1.36-1.59). The use of the multiple causes of death approach emphasized the contribution of 43 infectious diseases to mortality. 44 CONCLUSION: the results of the present study demonstrate an excess mortality from infection45 related diseases in patients affected by diabetes and, more interestingly, show a possible 46 underestimation of the impact of these conditions by routine mortality analyses

Prognostic Impact of Diabetes and Prediabetes on Survival Outcomes in Patients With Chronic Heart Failure: A Post-Hoc Analysis of the GISSI-HF (Gruppo Italiano per lo Studio della Sopravvivenza nella Insufficienza Cardiaca-Heart Failure) Trial

The independent prognostic impact of diabetes mellitus (DM) and prediabetes mellitus (pre-DM) on survival outcomes in patients with chronic heart failure has been investigated in observational registries and randomized, clinical trials, but the results have been often inconclusive or conflicting. We examined the independent prognostic impact of DM and pre-DM on survival outcomes in the GISSI-HF (Gruppo Italiano per lo Studio della Sopravvivenza nella Insufficienza Cardiaca-Heart Failure) trial

Sex differences in the association of psychological status with measures of physical activity and sedentary behaviour in adults with type 2 diabetes

Aim – To assess the association of psychological variables on leisure time physical activity and sedentary time in men and women with type 2 diabetes mellitus (T2D). Methods – In this cross-sectional study, we evaluated 163 patients with T2D, consecutively recruited at the Diabetes Centre of the Verona General Hospital. Scores on depression and anxiety symptoms, psychosocial factors (including self-efficacy, perceived interference, perceived severity, social support, misguided support behaviour, spouse’s positive behaviour), physical activity and time spent sitting were ascertained using questionnaires responses to the Beck Depression Inventory-II, Beck Anxiety Inventory, Multidimensional Diabetes Questionnaire, International Physical Activity Questionnaire. Results – Physical activity was significantly associated with higher social support in women, and with increased self-efficacy in men. Sedentary time was significantly associated with higher perceived interference, anxiety and depressive symptoms, and with reduced diabetes self-efficacy in women, while it was associated solely with anxiety in men. Depressive symptoms and self-efficacy in women and anxiety symptoms in men were independent predictors of sedentary time when entered in a multivariable regression model also including age, BMI, hemoglobin A1c, diabetes duration, perceived interference and self-efficacy as covariates. Conclusions – Lower self-efficacy and higher symptoms of depression were closely associated with increased sedentary time in women, but not in men, with T2D. It is possible that individualized behavioral interventions designed to reduce depressive symptoms and to improve diabetes self-efficacy would ultimately reduce sedentary behaviours, particularly in women with T2D

Abstracts of 51st EASD Annual Meeting

Background and aims: Presence and frequency of beta cell (BC) dysfunction(BCD) and insulin resistance (IR) in patients with newly diagnosedtype 2 diabetes mellitus (NDT2D) are imperfectly known, becauseprevious studies used small cohorts and/or only surrogate indexes of BCfunction and IR.We sought to assess BC function and IR with state-of-artmethods in the VNDS.Materials and methods: In 712 GADA-negative, drug naïve, consecutiveItalian NDT2D patients we assessed: 1. standard parameters; 2. insulinsensitivity (IS) by the euglycaemic insulin clamp); 3. BC functionby state-of-art modeling of prolonged (5 hours) OGTT-derived glucose/C-peptide curves. Thresholds for BCD and IR were the 25th percentilesof BC function and IS assessed with the same methods of the VNDS inItalian subjects with normal glucose regulation of the GENFIEV (n=340)and GISIR (n=386) studies, respectively.Results: In the VNDS, 89.8% [95% C.I.: 87.6 - 92.0%] and87.8% [85.4 - 90.2] patients had BCD and IR, respectively. Patientswith only one defect were 19.7% [16.8 - 22.6]. IsolatedBCD and isolated IR were present in 10.9% [8.6 - 13.2] and8.9% [6.8 - 11.0] patients, respectively. Coexistence of BCDand IR was observed in 78.9% [75.9 - 81.9] of the patients.1.4% [0.5 - 2.3] of the patients had no detectable alterations inBC function and IS. Patients (19.7%) with only one metabolicdefect had lower BMI, fasting glucose, HbA1c, triglycerides andBC function, and higher HDL-cholesterol and IS than patientswith both BCD and IR (p<0.01 or less after Bonferroni’scorrection).Conclusion: In conclusion, in NDT2DM patients: 1. at least 75.9% haveboth BCD and IR; 2. At least 87.6% and 85.4% have BCD and IR,respectively; 3. At least 16.8% have only one defect and a significantlydifferent (milder) metabolic phenotype compared to patients with bothdefects. These findings may be relevant to therapeutic strategies centeredon the metabolic phenotype of the patient.Clinical Trial Registration Number: NCT00879801; NCT01526720Supported by: University of Veron