Hepatokines and MASLD: The GLP1-Ras-FGF21-Fetuin-A Crosstalk as a Therapeutic Target.

The introduction of the term "Metabolic Steatotic Liver Disease" (MASLD) underscores the critical role of metabolic dysfunction in the development and progression of chronic liver disease and emphasizes the need for strategies that address both liver disease and its metabolic comorbidities. In recent years, a liver-focused perspective has revealed that altered endocrine function of the fatty liver is a key contributor to the metabolic dysregulation observed in MASLD. Due to its secretory capacity, the liver's increased production of proteins known as "hepatokines" has been linked to the development of insulin resistance, explaining why MASLD often precedes dysfunction in other organs and ultimately contributes to systemic metabolic disease. Among these hepatokines, fibroblast growth factor 21 (FGF21) and fetuin-A play central roles in regulating the metabolic abnormalities associated with MASLD, explaining why their dysregulated secretion in response to metabolic stress has been implicated in the metabolic abnormalities of MASLD. This review postulates why their modulation by GLP1-Ras may mediate the beneficial metabolic effects of these drugs, which have increased attention to their emerging role as pharmacotherapy for MASLD. By discussing the crosstalk between GLP1-Ras-FGF21-fetuin-A, this review hypothesizes that the possible modulation of fetuin-A by the novel GLP1-FGF21 dual agonist pharmacotherapy may contribute to the management of metabolic and liver diseases. Although research is needed to go into the details of this crosstalk, this topic may help researchers explore the mechanisms by which this type of pharmacotherapy may manage the metabolic dysfunction of MASLD.

Short-term gut microbiota's shift after laparoscopic Roux-en-Y vs one anastomosis gastric bypass: results of a multicenter randomized control trial.

BACKGROUND: Roux-en-Y (RYGB) and one anastomosis gastric bypass (OAGB) represent two of the most used bariatric/metabolic surgery (BMS) procedures. Gut microbiota (GM) shift after bypass surgeries, currently understated, may be a possible key driver for the short- and long-term outcomes. METHODS: Prospective, multicenter study enrolling patients with severe obesity, randomized between OAGB or RYGB. Fecal and blood samples were collected, pre- (T0) and 24 months postoperatively (T1). GM was determined by V3-V4 16S rRNA regions sequencing and home-made bioinformatic pipeline based on Qiime2 plugin and R packages. OBJECTS: To compare OAGB vs RYGB microbiota profile at T1 and its impact on metabolic and nutritional status. RESULTS: 54 patients completed the study, 27 for each procedure. An overall significant variation was detected in anthropometric and serum nutritional parameters at T1, with a significant, similar decrease in overall microbial alpha and beta diversity observed in both groups. An increase in relative abundances of Actinobacteria and Proteobacteria and a reduction of Bacteroidetes, no significant changes in Firmicutes and Verrucomicrobia, with an increase of the Firmicutes/Bacteroidetes ratio were observed. CONCLUSIONS: BMS promotes a dramatic change in GM composition. This is the first multicenter, RCT evaluating the impact of OAGB vs Roux-en-Y bypass on GM profile. The bypass technique per se did not impact differently on GM or other examined metabolic parameters. The emergence of slightly different GM profile postoperatively may be related to clinical conditions or may influence medium or long-term outcomes and as such GM profile may represent a biomarker for bariatric surgery's outcomes.

The intricate relationship between obesity, type 2 diabetes and female breast cancer: A retrospective study of 335 women.

Background: Type 2 diabetes (T2D) is a risk factor for female breast cancer (FBC). Obesity has also been associated with FBC, also depending on menopausal status. This study aimed to evaluate the impact of obesity and T2D on the development, aggressiveness, and invasiveness of FBC. Methods: Demographic, clinical, and histopathological data from 335 women with FBC were collected, and analyzed according to weight category (102 normal weight, 117 overweight, and 116 living with obesity) and the presence/absence of T2D. Results: Age at oncologic diagnosis was not statistically significantly different for body weight; women with overweight or obesity were more likely to have an oncologic diagnosis after menopause than normal weight (p < 0.001). The presence of overweight/obesity and T2D seemed to be associated with a higher incidence of metastasis, recurrence, and triple-negative breast cancer (TNBC) subtype (p < 0.001). Excess body weight was also associated with high histologic grade (G3) (p < 0.005). Conclusions: These results confirm excess body weight and T2D as unfavorable prognostic factors in terms of the presence of the TNBC subtype, tumor metastasis, recurrence, and aggressiveness (G3 and Ki-67 > 20%). This study highlights the importance of prevention in all women, with early screening, and adequate nutritional programs.

Remission of type 2 diabetes: position statement of the Italian society of diabetes (SID).

The primary cause of the pandemic scale of type 2 diabetes (T2D) is the excessive and/or abnormal accumulation of adiposity resulting from a chronic positive energy balance. Any form of weight loss dramatically affects the natural history of T2D, favoring prevention, treatment, and even remission in the case of significant weight loss. However, weight regain, which is often accompanied by the recurrence or worsening of obesity complications such as T2D, is an inevitable biological phenomenon that is an integral part of the pathophysiology of obesity. This can occur not only after weight loss, but also during obesity treatment if it is not effective enough to counteract the physiological responses aimed at restoring adiposity to its pre-weight-loss equilibrium state. Over the past few years, many controlled and randomized studies have suggested a superior efficacy of bariatric surgery compared to conventional therapy in terms of weight loss, glycemic control, and rates of T2D remission. Recently, the therapeutic armamentarium in the field of diabetology has been enriched with new antihyperglycemic drugs with considerable efficacy in reducing body weight, which could play a pathogenetic role in the remission of T2D, not through the classical incretin effect, but by improving adipose tissue functions. All these concepts are discussed in this position statement, which aims to deepen the pathogenetic links between obesity and T2D, shift the paradigm from a "simple" interaction between insulin resistance and insulin deficiency, and evaluate the efficacy of different therapeutic interventions to improve T2D management and induce diabetes remission whenever still possible.

Sex-Differences in Response to Treatment with Liraglutide 3.0 mg.

Background: Sex differences characterize the prevalence and attitudes toward weight management. Despite limited evidence suggesting greater weight loss in women with anti-obesity pharmacotherapy, sex-specific analysis remains underexplored. This retrospective study aimed to evaluate the sex-specific response to liraglutide 3.0 mg treatment in people with obesity without type 2 diabetes (T2D). Methods: Data were collected from 47 patients (31 women, 16 men) with age > 18 years; BMI ≥ 30 kg/m2; absence of T2D; and exclusion of prior anti-obesity treatment, comorbidities, or bariatric surgery. Only patients who maintained the liraglutide 3.0 mg dose for at least 6 months were included. Results: Both sexes showed significant reductions in weight and BMI at 3 and 6 months. Men achieved greater weight loss (WL), BMI reduction, %WL, WL > 5%, and >10% than women, and they also showed more significant improvements in metabolic parameters (total and LDL cholesterol, Fibrosis-4 Index FIB-4). No significant sex differences were observed in glucose metabolism or renal function. Conclusions: This study showed a greater therapeutic effect of liraglutide 3.0 mg in men. Given men's higher risk of cardiovascular disease (CVD), and underrepresentation in clinical weight loss programs, these findings may increase male engagement and improve their CVD risk.

Female obesity: clinical and psychological assessment toward the best treatment.

Obesity is a heterogeneous condition which results from complex interactions among sex/gender, sociocultural, environmental, and biological factors. Obesity is more prevalent in women in most developed countries, and several clinical and psychological obesity complications show sex-specific patterns. Females differ regarding fat distribution, with males tending to store more visceral fat, which is highly correlated to increased cardiovascular risk. Although women are more likely to be diagnosed with obesity and appear more motivated to lose weight, as confirmed by their greater representation in clinical trials, males show better outcomes in terms of body weight and intra-abdominal fat loss and improvements in the metabolic risk profile. However, only a few relatively recent studies have investigated gender differences in obesity, and sex/gender is rarely considered in the assessment and management of the disease. This review summarizes the evidence of gender differences in obesity prevalence, contributing factors, clinical complications, and psychological challenges. In addition, we explored gender differences in response to obesity treatments in the specific context of new anti-obesity drugs.

Validation in type 2 diabetes of a metabolomic signature of all-cause mortality.

CONTEXT: Mortality in type 2 diabetes is twice that of the normoglycemic population. Unravelling biomarkers that identify high-risk patients for referral to the most aggressive and costly prevention strategies is needed. OBJECTIVE: To validate in type 2 diabetes the association with all-cause mortality of a 14-metabolite score (14-MS) previously reported in the general population and whether this score can be used to improve well-established mortality prediction models. METHODS: This is a sub-study consisting of 600 patients from the "Sapienza University Mortality and Morbidity Event Rate" (SUMMER) study in diabetes, a prospective multicentre investigation on all-cause mortality in patients with type 2 diabetes. Metabolic biomarkers were quantified from serum samples using high-throughput proton nuclear magnetic resonance metabolomics. RESULTS: In type 2 diabetes, the 14-MS showed a significant (p < 0.0001) association with mortality, which was lower (p < 0.0001) than that reported in the general population. This difference was mainly due to two metabolites (histidine and ratio of polyunsaturated fatty acids to total fatty acids) with an effect size that was significantly (p = 0.01) lower in diabetes than in the general population. A parsimonious 12-MS (i.e. lacking the 2 metabolites mentioned above) improved patient discrimination and classification of two well-established mortality prediction models (p < 0.0001 for all measures). CONCLUSIONS: The metabolomic signature of mortality in the general population is only partially effective in type 2 diabetes. Prediction markers developed and validated in the general population must be revalidated if they are to be used in patients with diabetes.

MASLD, hepatic steatosis and fibrosis are associated with the prevalence of chronic kidney disease and retinopathy in adults with type 1 diabetes mellitus.

AIM: We examined whether metabolic dysfunction-associated steatotic liver disease (MASLD) with or without significant fibrosis (assessed by validated non-invasive biomarkers) was associated with an increased risk of prevalent chronic kidney disease (CKD) or diabetic retinopathy in people with type 1 diabetes mellitus (T1DM). METHODS: We performed a retrospective multicenter cross-sectional study involving 1,409 adult outpatients with T1DM, in whom hepatic steatosis index (HSI) and fibrosis (FIB)-4 index were calculated for non-invasively detecting hepatic steatosis (defined by HSI > 36), with or without coexisting significant fibrosis (FIB-4 index ≥ 1.3 or < 1.3). CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 or urine albumin/creatinine ratio ≥ 3.0 mg/mmol. The presence of diabetic retinopathy was also recorded in all participants. RESULTS: Patients with MASLD and significant fibrosis (n = 93) had a remarkably higher prevalence of CKD and diabetic retinopathy than their counterparts with MASLD without fibrosis (n = 578) and those without steatosis (n = 738). After adjustment for sex, diabetes duration, hemoglobin A1c, hypertension, and use of antihypertensive or lipid-lowering medications, patients with SLD and significant fibrosis had a higher risk of prevalent CKD (adjusted-odds ratio 1.76, 95 % confidence interval 1.05-2.96) than those without steatosis. Patients with MASLD without fibrosis had a higher risk of prevalent retinopathy (adjusted-odds ratio 1.49, 95 % CI 1.13-1.46) than those without steatosis. CONCLUSION: This is the largest cross-sectional study showing that MASLD with and without coexisting significant fibrosis was associated, independently of potential confounders, with an increased risk of prevalent CKD and retinopathy in adults with T1DM.

Reduced Lipopolysaccharide-Binding Protein (LBP) Levels Are Associated with Non-Alcoholic Fatty Liver Disease (NAFLD) and Adipose Inflammation in Human Obesity.

Lipopolysaccharide (LPS) and its binding protein LBP have emerged as potential contributors to the progression from overweight/obesity to overt metabolic diseases and NAFLD. While LPS is known to activate hepatocyte inflammation, thus contributing toward NAFLD development, the role of LBP is more intricate, and recent data have shown that experimental reduction in hepatic LBP promotes NAFLD progression. In this cross-sectional investigation, we evaluated circulating LBP in relation to obesity, NAFLD, visceral adipose tissue (VAT) inflammation, and type 2 diabetes (T2D). We recruited 186 individuals (M/F: 81/105; age: 47 ± 10.4 years; BMI: 35.5 ± 8.6 kg/m2); a subgroup (n = 81) underwent bariatric surgery with intra-operative VAT and liver biopsies. LBP levels were higher in obese individuals than non-obese individuals but were inversely correlated with the parameters of glucose metabolism. Reduced LBP predicted T2D independent of age, sex, and BMI (p < 0.001). LBP levels decreased across more severe stages of hepatosteatosis and lobular inflammation, and were inversely associated with VAT inflammation signatures. In conclusion, LBP levels are increased in obese individuals and are associated with a more favorable metabolic profile and lower NAFLD/NASH prevalence. A possible explanation for these findings is that hepatic LBP production may be triggered by chronic caloric excess and facilitate LPS degradation in the liver, thus protecting these individuals from the metabolic consequences of obesity.

Association between different modalities of insulin administration and metabolic dysfunction-associated fatty liver disease in adults with type 1 diabetes mellitus.

AIM: We examined whether different insulin administration modalities, i.e., multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII by insulin pumps), are differently associated with the risk of having metabolic dysfunction-associated fatty liver disease (MAFLD), with or without coexisting significant liver fibrosis (assessed by validated non-invasive biomarkers), in adults with type 1 diabetes mellitus (T1DM). METHODS: We conducted a retrospective, multicenter, cross-sectional study involving 1,417 adult individuals with established T1DM treated with MDI or CSII. We calculated hepatic steatosis index (HSI) and fibrosis (FIB)-4 index for non-invasively detecting MAFLD (defined by HSI >36), with or without coexisting significant fibrosis (defined by FIB-4 index ≥ 1.3 or <1.3, respectively). RESULTS: Compared to the MDI group (n = 1,161), insulin-pump users (n = 256; 18.1%) were more likely to be younger (mean age: 40 vs. 48 years, P < 0.001), had better glycemic control (mean hemoglobin A1c: 7.7%  vs. 7.9%, P = 0.025) and a markedly lower prevalence of MAFLD with coexisting significant fibrosis (2.7%  vs. 8.1%, P = 0.010), but a comparable prevalence of MAFLD without fibrosis. In multinomial logistic regression analysis, CSII therapy was associated with a ∼70%-lower risk of MAFLD with significant fibrosis (unadjusted odds ratio 0.32, 95% confidence interval 0.14-0.70; P = 0.004), but this association was no longer significant after adjustment for age, hemoglobin A1c and other potential confounders. CONCLUSION: The lower prevalence of MAFLD with coexisting significant fibrosis we observed in adults with T1DM using CSII therapy, compared to those using MDI therapy, is primarily mediated by inter-group differences in age.

Hepatic steatosis with significant fibrosis is associated with an increased 10-year estimated risk of cardiovascular disease in adults with type 1 diabetes mellitus.

BACKGROUND: We assessed whether hepatic steatosis with or without significant fibrosis (determined by validated non-invasive biomarkers) is associated with an increased 10-year estimated risk for cardiovascular disease (CVD) in people with type 1 diabetes mellitus (T1DM). METHODS: We conducted a retrospective, multicenter, cross-sectional study involving 1,254 adults with established T1DM without pre-existing CVD. We used the hepatic steatosis index (HSI) and fibrosis (FIB)-4 index for non-invasively detecting hepatic steatosis (defined as HSI > 36), with or without coexisting significant fibrosis (defined as FIB-4 index ≥ 1.3 or < 1.3). We calculated the Steno type 1 risk engine and the atherosclerotic CVD (ASCVD) risk score to estimate the 10-year risk of developing a first fatal or nonfatal CVD event. RESULTS: Using the Steno type 1 risk engine, a significantly greater proportion of patients with hepatic steatosis and significant fibrosis (n = 91) had a high 10-year estimated CVD risk compared to those with hepatic steatosis alone (n = 509) or without steatosis (n = 654) (75.8% vs. 23.2% vs. 24.9%, p < 0.001). After adjustment for sex, BMI, diabetes duration, hemoglobin A1c, chronic kidney disease, and lipid-lowering medication use, patients with hepatic steatosis and significant fibrosis had an increased 10-year estimated risk of developing a first fatal or nonfatal CVD event (adjusted-odds ratio 11.4, 95% confidence interval 3.54-36.9) than those without steatosis. We observed almost identical results using the ASCVD risk calculator. CONCLUSIONS: The 10-year estimated CVD risk is remarkably greater in T1DM adults with hepatic steatosis and significant fibrosis than in their counterparts with hepatic steatosis alone or without steatosis.

Association of osteocalcin, osteoprotegerin, and osteopontin with cardiovascular disease and retinopathy in type 2 diabetes.

BACKGROUND: Novel biomarkers of vascular disease in diabetes could help identify new mechanistic pathways. Osteocalcin, osteoprotegerin, and osteopontin are key molecules involved in bone and vascular calcification processes, both of which are compromised in diabetes. We aimed to evaluate possible associations of osteocalcin, osteoprotegerin, and osteopontin with cardiovascular disease (CVD) and diabetic retinopathy (DR) among people with type 2 diabetes (T2D). MATERIALS AND METHODS: Osteocalcin, osteoprotegerin, and osteopontin concentrations were measured at enrolment in 848 participants with T2D from the Sapienza University Mortality and Morbidity Event Rate (SUMMER) Study (ClinicalTrials.gov: NCT02311244). Logistic regression models and propensity score matching were used to assess possible associations of osteocalcin, osteoprotegerin, and osteopontin with a history of CVD and with evidence of any grade of DR adjusting for confounders. RESULTS: Previous CVD was reported in 139 (16.4%) participants, while 144 (17.0%) had DR. After adjusting for possible confounders, osteocalcin but not osteoprotegerin or osteopontin concentrations were associated with a history of CVD (Odds Ratio [OR] and 95% CI for one standard deviation (SD) increase in osteocalcin concentrations (natural log): 1.35 (1.06-1.72), p = 0.014). Associations with prevalent DR were seen for osteoprotegerin (OR for one SD increase in osteoprotegerin concentrations (natural log): 1.25 (1.01-1.55), p = 0.047) and osteopontin (OR for one SD increase in osteopontin concentrations (natural log): 1.25 (1.02-1.53), p = 0.022), but not osteocalcin. CONCLUSIONS: In T2D, higher serum osteocalcin concentrations are associated with macrovascular complications and higher osteoprotegerin and osteopontin concentrations with microvascular complications, suggesting that these osteokines might be involved in pathways directly related to vascular disease.

Sex Differences in Cardiovascular Disease and Cardiovascular Risk Estimation in Patients With Type 1 Diabetes.

CONTEXT: Patients with type 1 diabetes (T1D) have higher cardiovascular disease (CVD) risk than the general population. OBJECTIVE: This observational study aims to evaluate sex-related differences in CVD prevalence and CVD risk estimates in a large cohort of T1D adults. METHODS: We conducted a multicenter, cross-sectional study involving 2041 patients with T1D (mean age 46 years; 44.9% women). In patients without pre-existing CVD (primary prevention), we used the Steno type 1 risk engine to estimate the 10-year risk of developing CVD events. RESULTS: CVD prevalence (n = 116) was higher in men than in women aged ≥55 years (19.2 vs 12.8%, P = .036), but comparable between the 2 sexes in those aged <55 years (P = .91). In patients without pre-existing CVD (n = 1925), mean 10-year estimated CVD risk was 15.4 ± 0.4% without any significant sex difference. However, stratifying this patient group by age, the 10-year estimated CVD risk was significantly higher in men than in women until age 55 years (P < .001), but this risk equalized after this age. Carotid artery plaque burden was significantly associated with age ≥55 years and with a medium and high 10-year estimated CVD risk, without any significant sex difference. Diabetic retinopathy and sensory-motor neuropathy were also associated with higher 10-year CVD risk and female sex. CONCLUSION: Both men and women with T1D are at high CVD risk. The 10-year estimated CVD risk was higher in men aged <55 years than in women of similar age, but these sex differences disappeared at age ≥55 years, suggesting that female sex was no longer protective.

The three facets of the SARS-CoV-2 pandemic during the first two waves in the northern, central, and southern Italy.

BACKGROUND: There is a scarcity of information in literature regarding the clinical differences and comorbidities of patients affected by Coronavirus disease 2019 (COVID-19), which could clarify the different prevalence of the outcomes (composite and only death) between several Italian regions. OBJECTIVE: This study aimed to assess the heterogeneity of clinical features of patients with COVID-19 upon hospital admission and disease outcomes in the northern, central, and southern Italian regions. METHODS: An observational cohort multicenter retrospective study including 1210 patients who were admitted for COVID-19 in Infectious diseases, Pulmonology, Endocrinology, Geriatrics and Internal Medicine Units in Italian cities stratified between north (263 patients); center (320 patients); and south (627 patients), during the first and second pandemic waves of SARS-CoV-2 (from February 1, 2020 to January 31, 2021). The data, obtained from clinical charts and collected in a single database, comprehended demographic characteristics, comorbidities, hospital and home pharmacological therapies, oxygen therapy, laboratory values, discharge, death and Intensive care Unit (ICU) transfer. Death or ICU transfer were defined as composite outcomes. RESULTS: Male patients were more frequent in the northern Italian region than in the central and southern regions. Diabetes mellitus, arterial hypertension, chronic pulmonary and chronic kidney diseases were the comorbidities more frequent in the southern region; cancer, heart failure, stroke and atrial fibrillation were more frequent in the central region. The prevalence of the composite outcome was recorded more frequently in the southern region. Multivariable analysis showed a direct association between the combined event and age, ischemic cardiac disease, and chronic kidney disease, in addition to the geographical area. CONCLUSIONS: Statistically significant heterogeneity was observed in patients with COVID-19 characteristics at admission and outcomes from northern to southern Italy. The higher frequency of ICU transfer and death in the southern region may depend on the wider hospital admission of frail patients for the availability of more beds since the burden of COVID-19 on the healthcare system was less intense in southern region. In any case, predictive analysis of clinical outcomes should consider that the geographical differences that may reflect clinical differences in patient characteristics, are also related to access to health-care facilities and care modalities. Overall, the present results caution against generalizability of prognostic scores in COVID-19 patients derived from hospital cohorts in different settings.

Liver fibrosis is associated with impaired bone mineralization and microstructure in obese individuals with non-alcoholic fatty liver disease.

BACKGROUND AND PURPOSE: Chronic liver diseases are associated with increased bone fracture risk, mostly in end-stage disease and cirrhosis; besides, data in non-alcoholic fatty liver disease (NAFLD) are limited. Aim of this study was to investigate bone mineralization and microstructure in obese individuals with NAFLD in relation to the estimated liver fibrosis. METHODS: For this cross-sectional investigation, we analyzed data from 1872 obese individuals (44.6 ± 14.1 years, M/F: 389/1483; BMI: 38.3 ± 5.3 kg/m2) referring to the Endocrinology outpatient clinics of Sapienza University, Rome, Italy. Participants underwent clinical work-up, Dual-Energy X-ray Absorptiometry for assessing bone mineral density (BMD) and microarchitecture (trabecular bone score, TBS). Liver fibrosis was estimated by Fibrosis Score 4 (FIB-4). Serum parathyroid hormone (PTH), 25(OH) vitamin D, osteocalcin and IGF-1 levels were measured. RESULTS: Obese individuals with osteopenia/osteoporosis had greater FIB-4 than those with normal BMD (p < 0.001). FIB-4 progressively increased in presence of degraded bone microarchitecture (p < 0.001) and negatively correlated with the serum osteocalcin (p < 0.001) and IGF-1 (p < 0.001), which were both reduced in presence of osteopenia/osteoporosis. FIB-4 predicted IGF-1 reduction in multivariable regression models adjusted for confounders (ß: - 0.18, p < 0.001). Higher FIB-4 predicted bone fragility with OR 3.8 (95%C.I:1.5-9.3); this association persisted significant after adjustment for sex, age, BMI, diabetes, smoking status and PTH at the multivariable logistic regression analysis (OR 1.91 (95%C.I:1.15-3.17), p < 0.01), with AUROC = 0.842 (95%C.I:0.795-0.890; p < 0.001). CONCLUSION: Our data indicate the presence of a tight relation between NAFLD-related liver fibrosis, lower bone mineral density and degraded microarchitecture in obese individuals, suggesting potential common pathways underlying liver and bone involvement in obesity and insulin resistance-associated disorders.

Contribution of rare variants in monogenic diabetes-genes to early-onset type 2 diabetes.

AIM: This study investigated whether rare, deleterious variants in monogenic diabetes-genes are associated with early-onset type 2 diabetes (T2D). METHODS: A nested case-control study was designed from 9712 Italian patients with T2D. Individuals with age at diabetes onset ≤35 yrs (n = 300; cases) or ≥65 yrs (n = 300; controls) were selected and screened for variants in 27 monogenic diabetes-genes by targeted resequencing. Rare (minor allele frequency-MAF <1%) and possibly deleterious variants were collectively tested for association with early-onset T2D. The association of a genetic risk score (GRS) based on 17 GWAS-SNPs for T2D was also tested. RESULTS: When all rare variants were considered together, each increased the risk of early-onset T2D by 65% (allelic OR =1.64, 95% CI: 1.08-2.48, p = 0.02). Effects were similar when the 600 study participants were stratified according to their place of recruitment (Central-Southern Italy, 182 cases vs. 142 controls, or Rome urban area, 118 vs. 158, p for heterogeneity=0.53). Progressively less frequent variants showed increasingly stronger effects in the risk of early-onset T2D for those with MAF <0.001% (OR=6.34, 95% CI: 1.87-22.43, p = 0.003). One unit of T2D-GRS significantly increased the risk of early-onset T2D (OR 1.09, 95% CI: 1.01-1.18; p = 0.02). This association was stronger among rare variants carriers as compared to non-carriers (p = 0.02). CONCLUSION: Rare variants in monogenic-diabetes genes are associated with an increased risk of early-onset T2D, and interact with common T2D susceptibility variants in shaping it. These findings might help develop prediction tools to identify individuals at high risk of developing T2D in early adulthood.

Deep Resequencing of 9 Candidate Genes Identifies a Role for ARAP1 and IGF2BP2 in Modulating Insulin Secretion Adjusted for Insulin Resistance in Obese Southern Europeans.

Type 2 diabetes is characterized by impairment in insulin secretion, with an established genetic contribution. We aimed to evaluate common and low-frequency (1-5%) variants in nine genes strongly associated with insulin secretion by targeted sequencing in subjects selected from the extremes of insulin release measured by the disposition index. Collapsing data by gene and/or function, the association between disposition index and nonsense variants were significant, also after adjustment for confounding factors (OR = 0.25, 95% CI = 0.11-0.59, p = 0.001). Evaluating variants individually, three novel variants in ARAP1, IGF2BP2 and GCK, out of eight reaching significance singularly, remained associated after adjustment. Constructing a genetic risk model combining the effects of the three variants, only carriers of the ARAP1 and IGF2BP2 variants were significantly associated with a reduced probability to be in the lower, worst, extreme of insulin secretion (OR = 0.223, 95% CI = 0.105-0.473, p < 0.001). Observing a high number of normal glucose tolerance between carriers, a regression posthoc analysis was performed. Carriers of genetic risk model variants had higher probability to be normoglycemic, also after adjustment (OR = 2.411, 95% CI = 1.136-5.116, p = 0.022). Thus, in our southern European cohort, nonsense variants in all nine candidate genes showed association with better insulin secretion adjusted for insulin resistance, and we established the role of ARAP1 and IGF2BP2 in modulating insulin secretion.

Characterization of gut microbiota in patients with metabolic syndrome candidates for bariatric/metabolic surgery: Preliminary findings of a multi-center prospective study.

INTRODUCTION: gut microbiota (GM) seems to be involved in the pathophysiology and progression of both metabolic syndrome (MS) and obesity. The aim was to investigate GM's composition in patients with severe obesity, candidates for bariatric/metabolic surgery BMS. MATERIALS AND METHODS: Multicentre, prospective, cohort study, enrolling 84 patients with BMI 40-55 kg/m2, divided bymetabolic status (MS) inhealthy(group A), pre-MS (B), or MS (C). RESULTS: No differences were foundregarding anthropometric,nutritional parameters, except for vitamin D.As a whole the alpha and beta diversity examinations showed no statistical differences in GM profile. A total of 5/7 phyla with relative frequencies were identified above 0.1% (Actinobacteria,Bacteroidetes,Firmicutes,Proteobacteria,Verrucomicrobia).FusobacteriaandPatescibacteriarepresented the less abundant. There were no significant differences in the top ten genera.Data onBacteroidetes(inversely related to triglycerides and LDL and directly related to HDL levels) and onFirmicutes(opposite trend) relative abundances suggest no differences among the three conditions.No correlation between the relative abundance of themain phylaand plasmatic glucose levels was observed. CONCLUSIONS: In a selected cohort of patients with obesity, MS did not affect the preoperative GM's profile. Severe obesity, per se, seems to be an independent condition affecting GM.