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Background: Achieving optimal glycemic targets is the main therapeutic goal in patients with type 2 diabetes (T2D) mellitus. HbA1c is the reference biomarker for monitoring glycemic control; however, in specific conditions affecting erythrocyte turnover or in patients on multiple daily injection (MDI) insulin regimens, the determination of glycated albumin (GA) may be preferable. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors represent a novel class of antidiabetic drugs that lower plasma glucose concentrations quickly, with insulin-independent mechanisms. Herein, we explored the role of GA in predicting the short-term response to SGLT-2 inhibitors as add-on to MDI insulin., Methods: Sixteen patients with long-standing, poorly controlled T2D on MDI insulin starting an SGLT-2 inhibitor were subjected to plasma GA and HbA1c measurements at 30 days intervals for up to 3 months in order to examine the temporal changes of these glycemic biomarkers., Results: At the end of the study, grossly coincident with the life span of erythrocytes, a significant decrease in median HbA1c was observed, (from 8.7 [range: 8.2-9.3%] at baseline to 7.2 [range: 7.0-7.9%]), with the advantage of less insulin dose requirements. However, significant, and incremental reductions in median GA determinations could be already evident after 30 days (-3.5 [range: -7.5, -2.5%]) and 60 days (-6.4 [range: -10.5, -4.7%]) from the start of SGLT-2 inhibitor treatment and persisted for up to 3 months (-8.6 [range: -12.1, 6.1%]). The decrements of HbA1c observed at the 3-month visit were highly correlated with the concurrent absolute reductions of plasma GA (ρ=0.550, P=0.027), whereas a borderline significance could be demonstrated with reference to reductions in plasma GA at 30 and 60 days., Conclusions: Although limited by the small number of participants, these preliminary findings suggest that GA, rather than HbA1c, could represent a useful and reliable biomarker in T2D to monitor the early glucose-lowering effects of antidiabetic drugs with rapid onset of action, such as SGLT-2 inhibitors and MDI insulin.

Objective: Recently, the role of circulating miRNAs as non-invasive biomarkers for the identification and monitoring of diabetes microvascular complications has emerged. Herein, we aimed to: identify circulating miRNAs differentially expressed in patients with and without diabetic retinopathy (DR); examine their predictive value; and understand their pathogenic impact. Methods: Pooled serum samples from randomly selected matched patients with type 2 diabetes, either with or without DR, were used for initial serum miRNA profiling. Validation of the most relevant miRNAs was thereafter conducted by RT-qPCR in an extended sample of patients with DR and matched controls. Results: Following miRNA profiling, 43 miRNAs were significantly up- or down-regulated in patients with DR compared with controls. After individual validation, 5 miRNAs were found significantly overexpressed in patients with DR. One of them, miR-1281 , was the most up-regulated and appeared to be specifically related to DR. Furthermore, secreted levels of miR-1281 were increased in high glucose-cultured retinal cells, and there was evidence of a potential link between glucose-induced miR-1281 up-regulation and DR. Conclusion: Our findings suggest miR-1281 as a circulating biomarker of DR. Also, they highlight the pathogenic significance of miR-1281 , providing insights for a new potential target in treating DR., (Copyright © 2020 Greco, Chiefari, Accattato, Corigliano, Arcidiacono, Mirabelli, Liguori, Brunetti, Pullano, Scorcia, Fiorillo, Foti and Brunetti.)

Background: Type 2 diabetes mellitus (T2DM) is characterized by a prothrombotic state, predisposing to vascular complications. Some related markers, linking thrombophilia to hemostasis and inflammation, however, have been poorly explored in relation to patients' glycemia. We therefore investigated the association of laboratory hemostatic parameters, circulating adhesion molecules (ADMs), white blood cell (WBC) count, and neutrophil/lymphocyte ratio (NLR) with T2DM and glycemic control., Research Design: In this study, 82 subjects, grouped into T2DM patients ( n = 41) and healthy individuals ( n = 41) were enrolled. To evaluate glycemic control, the T2DM cohort was expanded to 133 patients and sub-classified according to glycated hemoglobin (HbA1c) <7% and ≥ 7% ( n = 58 and n = 75, respectively). We assessed glycemia, HbA1c, prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, plasminogen activator inhibitor-1 (PAI-1), platelet and leukocyte parameters, vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), and selectins (E-, P-, L-)., Results: PT % activity, PAI-1, VCAM-1, WBC, and neutrophil counts were significantly higher in T2DM patients than in healthy subjects. Poor glycemic control (HbA1c ≥ 7%) was correlated with increased PT activity ( p = 0.015), and higher levels of E-selectin ( p = 0.009), P-selectin ( p = 0.012), and NLR ( p = 0.019)., Conclusions: Both T2DM and poor glycemic control affect some parameters of hemostasis, inflammation, and adhesion molecules. Further studies are needed to establish their clinical utility as adjuvant markers for cardio-vascular risk in T2DM patients.

Background : Liraglutide is the first glucagon-like peptide-1 receptor agonist (GLP-1 RA) based on the human GLP-1 sequence, with potential weight loss benefits, approved for the treatment of type 2 diabetes (T2D) mellitus. Herein, we aimed to assess the 5-year effectiveness of Liraglutide in the management of weight and glycometabolic control in a Southern Italian cohort of overweight/obese T2D patients, who were naïve to GLP-1 RAs. Patients and Methods : Forty overweight or obese patients treated with Liraglutide at doses up to 1.8 mg/day, in combination with one or more oral antidiabetic agents, were retrospectively assessed at baseline, during, and after 60 months of continuous therapy. Results : After 5 years of Liraglutide treatment, body weight decreased from 92.1 ± 20.5 kg to 87.3 ± 20.0 Kg ( p < 0.001), with a mean reduction of 5.0 ± 7.0 Kg and a body mass index (BMI) decrement of -2.0 ± 3.1 Kg/m 2 . On Spearman's univariate analysis, change in body weight was correlated with female gender and baseline BMI. Hemoglobin A1c (HbA1c) decreased from 7.9 ± 0.9% at baseline to 7.0 ± 0.7% at the end of the study period ( p < 0.001), followed by a significant reduction in fasting plasma glucose. No significant differences emerged in other biochemical parameters, despite a trend toward improvement in lipid profile. Notwithstanding encouraging effects on several markers of cardiovascular disease (CVD), increments in the 5- and 10-year risk for the first atherosclerotic cardiovascular event were documented, as four incident cases of myocardial infarction. Conclusions : Prolonging treatment with Liraglutide can lead to durable benefits in relation to weight and glycemic control, with a greater impact on women. These results extend and corroborate previous observations, suggesting that gender per se may modulate the response to Liraglutide. Despite favorable effects on some established CVD risks factors, the long-term role of Liraglutide in primary prevention of CVD in patients with T2D remains controversial.

Background: SGLT-2 (sodium-glucose cotransporter-2) inhibitors are a novel class of oral hypoglycemic agents for the management of type 2 diabetes mellitus (T2DM). Herein, we aimed to assess the long-term effectiveness and safety of SGLT-2 inhibitors in a Southern Italy population of subjects affected by T2DM., Patients and Methods: 408 diabetic patients treated with one of the three SGLT-2 inhibitors currently available in Italy (dapagliflozin, empagliflozin, and canagliflozin), either alone or in combination with other antidiabetic drugs, were retrospectively assessed at baseline, during, and after 18 months of continuous therapy., Results: Treatment with SGLT-2 inhibitors resulted in a median decrease in HbA1c of 0.9%, with a percentage of decrement of 12 in relation to the baseline value, followed by a significant reduction ( P < 0.001) in fasting plasma glucose. Variations in HbA1c occurred independently of the baseline clinical or biochemical characteristics. In addition, treatment with SGLT-2 inhibitors reduced body weight ( P < 0.008) and decreased diastolic blood pressure ( P = 0.004). With regard to safety outcomes, 66 patients out of 91 stopped SGLT-2 inhibitors during follow-up because of chronic or recurring genital infections, while the rest experienced other adverse events, such as urinary tract infections, polyuria, nausea, hypotension, dizziness, acute coronary event, worsening of glycemic control status, and rapid deterioration of renal function., Conclusion: In our patients' population, the glycometabolic effects of SGLT-2 inhibitors were durable and comparable to those observed in multicenter randomized controlled trials. This notwithstanding safety concerns must be raised regarding the frequent occurrence of genitourinary infections and the risk of a rapid decline of renal function in patients with evidence of volume depletion and/or receiving other medications which can adversely affect kidney function., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2019 Maria Mirabelli et al.)

The high-mobility group A1 (HMGA1) gene has been previously identified as a potential novel candidate gene for susceptibility to insulin resistance and type 2 diabetes (T2D) mellitus. For this reason, several studies have been conducted in recent years examining the association of the HMGA1 gene variant rs146052672 (also designated IVS5-13insC) with T2D. Because of non-univocal data and non-overlapping results among laboratories, we conducted the current meta-analysis with the aim to yield a more precise and reliable conclusion for this association. Using predetermined inclusion criteria, MEDLINE, PubMed, Web of Science, Scopus, Google Scholar and Embase were searched for all relevant available literature published until November 2014. Two of the authors independently evaluated the quality of the included studies and extracted the data. Values from the single studies were combined to determine the meta-analysis pooled estimates. Heterogeneity and publication bias were also examined. Among the articles reviewed, five studies (for a total of 13,789 cases and 13,460 controls) met the predetermined criteria for inclusion in this meta-analysis. The combined adjusted odds ratio estimates revealed that the rs146052672 variant genotype had an overall statistically significant effect on increasing the risk of development of T2D. As most of the study subjects were Caucasian, further studies are needed to establish whether the association of this variant with an increased risk of T2D is generalizable to other populations. Also, in the light of this result, it would appear to be highly desirable that further in-depth investigations should be undertaken to elucidate the biological significance of the HMGA1 rs146052672 variant.

Background: Liraglutide is a glucagon-like peptide-1 receptor analog recently approved for the treatment of type 2 diabetes mellitus (T2DM). We aimed to assess the efficacy and safety of liraglutide versus glimepiride, as adjunct treatments to metformin, in achieving glycemic control in Italian patients with T2DM uncontrolled by metformin alone., Subjects and Methods: One hundred seventy-nine diabetes patients treated with metformin plus liraglutide (1.8 mg) or glimepiride (4 mg) were retrospectively assessed at baseline, during, and after 18 months of continuous therapy., Results: Treatment with liraglutide resulted in mean decreases in hemoglobin A1c (HbA1c) of -1.4%, when compared with glimepiride (-0.4%) (P < 0.001), and was followed by a significant reduction (P < 0.001) in fasting plasma glucose. Variations in HbA1c occurred independently from weight loss, which was significantly reduced (P < 0.001) in liraglutide-treated patients. The percentage of subjects reaching HbA1c levels below 7% or ≤ 6.5% was significantly different between the two treated groups (P < 0.001). Treatment with liraglutide reduced waist circumference (WC) (P < 0.001) and decreased both systolic and diastolic blood pressure (BP) (P < 0.001). It is interesting that the study also showed the impact of female gender in predicting a better glycemic response to liraglutide (P = 0.028)., Conclusions: Liraglutide was more effective than glimepiride in reducing HbA1c levels in treated patients with T2DM. This was evident in both genders, but particularly in women. Furthermore, liraglutide reduced body weight, WC, and BP, which are critical risk factors for cardiovascular disease.

Aims: To determine the prevalence of both prediabetes and type 2 diabetes mellitus (T2DM) by postpartum oral glucose tolerance test (ppOGTT) in Italian women diagnosed with gestational diabetes mellitus (GDM), and identify antepartum predictors of glucose intolerance., Methods: Retrospective study of 454 Caucasian women that underwent a 75g OGTT between 6 and 12 weeks postpartum in Calabria (Southern Italy) between 2004 and 2012. Prediabetes and T2DM were diagnosed according to the American Diabetes Association (ADA) criteria. Data were examined by univariate analysis and multiple regression analysis., Results: 290 women (63.9%) were normal, 146 (32.1%) had prediabetes (85 impaired fasting glycemia; 61 impaired glucose tolerance), and 18 (4.0%) had T2DM. Of the continuous variables, pre-pregnancy body mass index (BMI), age at pregnancy, fasting plasma glucose (FPG) at gravid OGTT, and week at diagnosis of GDM were associated with prediabetes and T2DM, whereas the parity was associated with T2DM only. For categorical traits, pre-pregnancy BMI ≥ 25 and previous diagnosis of polycystic ovary syndrome (PCOS) emerged as the strongest predictors of prediabetes whereas the strongest predictors of T2DM were FPG ≥ 100 mg/dl (5.6 mmol/l) at GDM diagnosis and pre-pregnancy BMI ≥ 25. Moreover, FPG at GDM screening was a good predictor of T2DM after receiver-operating-characteristic analysis., Conclusions: Our findings confirm the high prevalence of glucose intolerance in the early postpartum period in women with previous GDM. PCOS emerges as a new strong antepartum predictor of prediabetes., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: High-mobility group AT-hook 1 (HMGA1) is an important regulator of the insulin receptor gene. We have previously shown in three populations of white European ancestry that the HMGA1 gene variant rs146052672 (also designated IVS5-13insC) is associated with type 2 diabetes mellitus (T2DM). The aim of this study was to measure the frequency of this variant and to determine the degree of the association with T2DM and other features of the metabolic syndrome in a replication cohort of Hispanic Americans., Methods: This was a retrospective cohort study of well-characterized Hispanic-American participants analyzed in the Genomic Resource in Atherosclerosis (GRA) (Cardiovascular Research Institute, University of California, San Francisco). A total of 1144 individuals were studied, 320 of whom had T2DM. We examined associations of the rs146052672 SNP with T2DM, plasma lipids, lipoproteins, and body mass index (BMI)., Results: In this Hispanic-American cohort, the HMGA1 rs146052672 minor allele (C-insertion) frequency (MAF) was 21.4% with a carrier frequency of 37.4%, considerably higher than we previously observed among GRA white Europeans (MAF 3.1%). The prevalence of the IVS5-13insC variant was significantly higher in those with T2DM compared to controls [42.2% vs. 35.5%; odds ratio (OR) 1.44 95% confidence interval (CI) 1.09-1.90, P=0.011). The variant was also associated with BMI (positively, P=0.045) and plasma high-density lipoprotein cholesterol (HDL-C) (negatively, P=0.047)., Conclusions: As we saw previously among white Europeans, a functional HMGA1 variant was associated with T2DM in individuals of Hispanic-American ethnicity and was present at a much higher frequency.

Type 2 diabetes mellitus (DM) is a common metabolic-endocrine disorder often associated with overweight or obesity. It is a complex disease determined by both predisposing genetic factors and non-genetic environmental factors and interactions between them, leading to impaired beta-cell insulin secretion and peripheral insulin resistance. Insulin resistance is a prominent feature of most patients with type 2 DM and obesity, resulting in a reduced response of target tissues (muscle, liver and fat) to both endogenous and exogenous insulin. There is considerable evidence that heredity is a major contributor to the insulin resistance of type 2 DM. Initially, among those destined to develop diabetes, the beta cells of the pancreas compensate with increased insulin secretion to maintain normal glucose tolerance. Type 2 DM develops when beta cells fail to compensate. Despite of the numerous studies in the recent years, the actual genetic causes of insulin resistance and type 2 DM have not yet been clearly elucidated. Through linkage and "genome-wide" studies, genes were identified most frequently associated with type 2 DM, such as TCF7L2, considered, until recently, the most important gene among those predisposing to type 2 DM. On the other hand, numerous candidate genes have been analyzed for genetic variants that increase susceptibility to type 2 DM. Several variants have been identified in many of these genes, including the insulin receptor gene, INSR, and other genes involved in adipogenesis and beta-cell insulin secretion. In this context, recently our group has identified a new gene involved in the pathogenesis of insulin resistance and type 2 DM: the HMGA1 gene. Functional genetic variants of the HMGA1 gene, capable of reducing the intracellular levels of INSR in insulin target tissues, were found in 10% of patients with type 2 DM in three distinct populations: Italian, North American and French.

Context: High-mobility group A1 (HMGA1) protein is a key regulator of insulin receptor (INSR) gene expression. We previously identified a functional HMGA1 gene variant in 2 insulin-resistant patients with decreased INSR expression and type 2 diabetes mellitus (DM)., Objective: To examine the association of HMGA1 gene variants with type 2 DM., Design, Settings, and Participants: Case-control study that analyzed the HMGA1 gene in patients with type 2 DM and controls from 3 populations of white European ancestry. Italian patients with type 2 DM (n = 3278) and 2 groups of controls (n = 3328) were attending the University of Catanzaro outpatient clinics and other health care sites in Calabria, Italy, during 2003-2009; US patients with type 2 DM (n = 970) were recruited in Northern California clinics between 1994 and 2005 and controls (n = 958) were senior athletes without DM collected in 2004 and 2009; and French patients with type 2 DM (n = 354) and healthy controls (n = 50) were enrolled at the University of Reims in 1992. Genomic DNA was either directly sequenced or analyzed for specific HMGA1 mutations. Messenger RNA and protein expression for HMGA1 and INSR were measured in both peripheral lymphomonocytes and cultured Epstein-Barr virus-transformed lymphoblasts from patients with type 2 DM and controls., Main Outcome Measures: The frequency of HMGA1 gene variants among cases and controls. Odds ratios (ORs) for type 2 DM were estimated by logistic regression analysis., Results: The most frequent functional HMGA1 variant, IVS5-13insC, was present in 7% to 8% of patients with type 2 DM in all 3 populations. The prevalence of IVS5-13insC variant was higher among patients with type 2 DM than among controls in the Italian population (7.23% vs 0.43% in one control group; OR, 15.77 [95% confidence interval {CI}, 8.57-29.03]; P < .001 and 7.23% vs 3.32% in the other control group; OR, 2.03 [95% CI, 1.51-3.43]; P < .001). In the US population, the prevalence of IVS5-13insC variant was 7.7% among patients with type 2 DM vs 4.7% among controls (OR, 1.64 [95% CI, 1.05-2.57]; P = .03). In the French population, the prevalence of IVS5-13insC variant was 7.6% among patients with type 2 DM and 0% among controls (P = .046). In the Italian population, 3 other functional variants were observed. When all 4 variants were analyzed, HMGA1 defects were present in 9.8% of Italian patients with type 2 DM and 0.6% of controls. In addition to the IVS5 C-insertion, the c.310G>T (p.E104X) variant was found in 14 patients and no controls (Bonferroni-adjusted P = .01); the c.*82G>A variant (rs2780219) was found in 46 patients and 5 controls (Bonferroni-adjusted P < .001); the c.*369del variant was found in 24 patients and no controls (Bonferroni-adjusted P < .001). In circulating monocytes and Epstein-Barr virus-transformed lymphoblasts from patients with type 2 DM and the IVS5-13insC variant, the messenger RNA levels and protein content of both HMGA1 and the INSR were decreased by 40% to 50%, and these defects were corrected by transfection with HMGA1 complementary DNA., Conclusions: Compared with healthy controls, the presence of functional HMGA1 gene variants in individuals of white European ancestry was associated with type 2 DM.

Processed pseudogenes are non-functional copies of normal genes that arise by a process of mRNA retrotransposition. The human genome contains thousands of pseudogenes; however, knowledge regarding their biological role is limited. Previously, we demonstrated that high mobility group A1 (HMGA1) protein regulates the insulin receptor (INSR) gene and that two diabetic patients demonstrated a marked destabilization of HMGA1 mRNA. In this paper we report that this destabilization of HMGA1 mRNA is triggered by enhanced expression of RNA from an HMGA1 pseudogene, HMGA1-p. Targeted knockdown of HMGA1-p mRNA in patient cells results in a reciprocal increase in HMGA1 mRNA stability and expression levels with a parallel correction in cell-surface INSR expression and insulin binding. These data provide evidence for a regulatory role of an expressed pseudogene in humans and establishes a novel mechanistic linkage between pseudogene HMGA1-p expression and type 2 diabetes mellitus.

Type 2 diabetes mellitus is a widespread disease, affecting millions of people globally. Although genetics and environmental factors seem to have a role, the cause of this metabolic disorder is largely unknown. Here we report a genetic flaw that markedly reduced the intracellular expression of the high mobility group A1 (HMGA1) protein, and adversely affected insulin receptor expression in cells and tissues from four subjects with insulin resistance and type 2 diabetes. Restoration of HMGA1 protein expression in subjects' cells enhanced INSR gene transcription, and restored cell-surface insulin receptor protein expression and insulin-binding capacity. Loss of Hmga1 expression, induced in mice by disrupting the Hmga1 gene, considerably decreased insulin receptor expression in the major targets of insulin action, largely impaired insulin signaling and severely reduced insulin secretion, causing a phenotype characteristic of human type 2 diabetes.