The GLP-1 receptor agonists exenatide and liraglutide activate Glucose transport by an AMPK-dependent mechanism

Additional file 2: Figure S2. Effects of EXE on Glut-4 in cultured L6 myotubes. Myotubes were stimulated with 100 nmol/l EXE for 20 min or 48 h. Panel A shows qPCR of Glut-4 mRNA. In panel B is a representative western blot for Glut-4 and β-Actin (loading control). In panel C is a representative western blot for Glut-4 and β-IR (loading control) in plasma membrane (PM) extracts (Glut-4 translocation). For A and C panels, data are shown as fold increase over control ± SD of three independent experiments (*p < 0.001, vs Ctrl)

Are circulating Mg2+ levels associated with glucose tolerance profiles and incident type 2 diabetes?

Magnesium (Mg2+) is an enzyme co-factor that plays a key role in many biochemical reactions, as well as in glucose metabolism. Clinical evidences have demonstrated that depletion of serum Mg2+ increases exponentially with the duration of type 2 diabetes mellitus (T2DM). Diabetes is associated with low Mg2+, and hypomagnesemia is associated with insulin resistance, inflammation, and increased risk for cardiovascular disease. In subjects at high risk of inflammation and insulin resistance, supplementation of Mg2+ alone ameliorates both phenotypes, slowing the development and progression of hepatic steatosis. We analyze the relationship between serum Mg2+ levels and the onset of T2DM in a large cohort of well-characterized adult white individuals participating in the CATAMERI study, who were reexamined after a mean follow-up of 5.6 ± 0.9 years. In our analysis we acquired a significant negative correlation between Mg2+ levels, fasting glucose, and 2h-post load glucose in subjects who underwent an OGTT. Moreover, Mg2+ levels correlated negatively with fasting insulin levels, and positively with the lipid profile. As for the detrimental effect of lower circulating Mg2+ levels, our data revealed a significant reduction of T2DM risk of about 20% for each 1 mg/dL increase of circulating Mg2+. The present results are consistent with the theory that Mg2+ supplementation could ameliorate insulin sensitivity reducing the risk to develop T2DM

Reduced humoral response to two doses of COVID-19 vaccine in patients with inflammatory bowel disease: Data from ESCAPE-IBD, an IG-IBD study

Background Patients on immunosuppressive drugs have been excluded from COVID-19 vaccines trials, creating concerns regarding their efficacy. Aims To explore the humoral response to COVID-19 vaccines in patients with inflammatory bowel disease (IBD) Methods Effectiveness and Safety of COVID-19 Vaccine in Patients with Inflammatory Bowel Disease (IBD) Treated with Immunomodulatory or Biological Drugs (ESCAPE-IBD) is a prospective, multicentre study promoted by the Italian Group for the study of Inflammatory Bowel Disease. We present data on serological response eight weeks after the second dose of COVID-19 vaccination in IBD patients and healthy controls (HCs). Results 1076 patients with IBD and 1126 HCs were analyzed. Seropositivity for anti-SARS-CoV-2 IgG was reported for most IBD patients, even if with a lesser rate compared with HCs (92.1% vs. 97.9%; p&lt;0.001). HCs had higher antibody concentrations (median OD 8.72 [IQR 5.2-14-2]) compared to the whole cohort of IBD patients (median OD 1.54 [IQR 0.8-3.6]; p&lt;0.001) and the subgroup of IBD patients (n=280) without any treatment or on aminosalicylates only (median OD 1.72 [IQR 1.0–4.1]; p&lt;0.001). Conclusions Although most IBD patients showed seropositivity after COVID-19 vaccines, the magnitude of the humoral response was significantly lower than in HCs. Differently from other studies, these findings seem to be mostly unrelated to the use of immune-modifying treatments (ClinicalTrials.govID:NCT04769258)

A Functional Variant of the Dimethylarginine Dimethylaminohydrolase-2 Gene Is Associated with Insulin Sensitivity

Background: Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of endothelial nitric oxide synthase, which was associated with insulin resistance. Dimethylarginine dimethylaminohydrolase (DDAH) is the major determinant of plasma ADMA. Examining data from the DIAGRAM+ (Diabetes Genetics Replication And Meta-analysis), we identified a variant (rs9267551) in the DDAH2 gene nominally associated with type 2 diabetes (P =3610 25). Methodology/Principal Findings: initially, we assessed the functional impact of rs9267551 in human endothelial cells (HUVECs), observing that the G allele had a lower transcriptional activity resulting in reduced expression of DDAH2 and decreased NO production in primary HUVECs naturally carrying it. We then proceeded to investigate whether this variant is associated with insulin sensitivity in vivo. To this end, two cohorts of nondiabetic subjects of European ancestry were studied. In sample 1 (n = 958) insulin sensitivity was determined by the insulin sensitivity index (ISI), while in sample 2 (n = 527) it was measured with a euglycemic-hyperinsulinemic clamp. In sample 1, carriers of the GG genotype had lower ISI than carriers of the C allele (67633 vs.79644; P = 0.003 after adjusting for age, gender, and BMI). ADMA levels were higher in subjects carrying the GG genotype than in carriers of the C allele (0.6860.14 vs. 0.5760.14 mmol/l; P = 0.04). In sample 2, glucose disposal was lower in GG carriers as compared with C carriers (9.364.1 vs. 11.064.2 mg6Kg 21 free fat mass6min 21; P = 0.009)

Association of kidney disease measures with risk of renal function worsening in patients with type 1 diabetes

Background: Albuminuria has been classically considered a marker of kidney damage progression in diabetic patients and it is routinely assessed to monitor kidney function. However, the role of a mild GFR reduction on the development of stage 653 CKD has been less explored in type 1 diabetes mellitus (T1DM) patients. Aim of the present study was to evaluate the prognostic role of kidney disease measures, namely albuminuria and reduced GFR, on the development of stage 653 CKD in a large cohort of patients affected by T1DM. Methods: A total of 4284 patients affected by T1DM followed-up at 76 diabetes centers participating to the Italian Association of Clinical Diabetologists (Associazione Medici Diabetologi, AMD) initiative constitutes the study population. Urinary albumin excretion (ACR) and estimated GFR (eGFR) were retrieved and analyzed. The incidence of stage 653 CKD (eGFR &lt; 60 mL/min/1.73 m2) or eGFR reduction &gt; 30% from baseline was evaluated. Results: The mean estimated GFR was 98 \ub1 17 mL/min/1.73m2 and the proportion of patients with albuminuria was 15.3% (n = 654) at baseline. About 8% (n = 337) of patients developed one of the two renal endpoints during the 4-year follow-up period. Age, albuminuria (micro or macro) and baseline eGFR &lt; 90 ml/min/m2 were independent risk factors for stage 653 CKD and renal function worsening. When compared to patients with eGFR &gt; 90 ml/min/1.73m2 and normoalbuminuria, those with albuminuria at baseline had a 1.69 greater risk of reaching stage 3 CKD, while patients with mild eGFR reduction (i.e. eGFR between 90 and 60 mL/min/1.73 m2) show a 3.81 greater risk that rose to 8.24 for those patients with albuminuria and mild eGFR reduction at baseline. Conclusions: Albuminuria and eGFR reduction represent independent risk factors for incident stage 653 CKD in T1DM patients. The simultaneous occurrence of reduced eGFR and albuminuria have a synergistic effect on renal function worsening

Variants of Insulin-Signaling Inhibitor Genes in Type 2 Diabetes and Related Metabolic Abnormalities

Insulin resistance has a central role in the pathogenesis of several metabolic diseases, including type 2 diabetes, obesity, glucose intolerance, metabolic syndrome, atherosclerosis, and cardiovascular diseases. Insulin resistance and related traits are likely to be caused by abnormalities in the genes encoding for proteins involved in the composite network of insulin-signaling; in this review we have focused our attention on genetic variants of insulin-signaling inhibitor molecules. These proteins interfere with different steps in insulin-signaling: ENPP1/PC-1 and the phosphatases PTP1B and PTPRF/LAR inhibit the insulin receptor activation; INPPL1/SHIP-2 hydrolyzes PI3-kinase products, hampering the phosphoinositide-mediated downstream signaling; and TRIB3 binds the serine-threonine kinase Akt, reducing its phosphorylation levels. While several variants have been described over the years for all these genes, solid evidence of an association with type 2 diabetes and related diseases seems to exist only for rs1044498 of the ENPP1 gene and for rs2295490 of the TRIB3 gene. However, overall the data recapitulated in this Review article may supply useful elements to interpret the results of novel, more technically advanced genetic studies; indeed it is becoming increasingly evident that genetic information on metabolic diseases should be interpreted taking into account the complex biological pathways underlying their pathogenesis

The Triglycerides and Glucose (TyG) Index Is Associated with 1-Hour Glucose Levels during an OGTT

Background and Objectives: Among individuals with normal glucose tolerance (NGT), subjects with high levels of plasma glucose (&ge;155 mg/dL) at sixty minutes during an oral glucose tolerance test (1h-OGTT) are at an increased risk of developing type 2 diabetes. We investigated the association between the triglycerides and glucose (TyG) index, a novel marker of insulin resistance, with 1h-OGTT glucose plasma concentrations. Material and Methods: 1474 non-diabetic Caucasian subjects underwent a 75 g OGTT and were divided into two groups according to the cutoff 1h-OGTT plasma glucose &lt; 155 mg/dL (NGT-1h-low) and &ge; 155 mg/dL (NGT-1h-high). The TyG index was calculated as ln [fasting triglycerides (milligrams per deciliter) &times; fasting blood glucose (milligrams per deciliter)/2]. Multivariable linear and logistic regression analyses were used to establish the contribution of the TyG index to the variability of 1h-OGTT glucose, and how the former affected the risk of being NGT-1h-high. Results: 1004 individuals were NGT-1h-low and 470 were NGT-1h-high. The TyG index was higher for NGT-1h-high (p = 0.001) individuals, and it was an independent factor influencing 1h-OGTT glycemia (&beta; = 0.191, p &lt; 0.001) after correcting for age, sex, and BMI. The TyG index was the strongest marker associated with the risk of being NGT-1h-high (OR = 1.703, CI 95% 1.34&ndash;2.17, p &lt; 0.001) when compared with FPG (OR = 1.054, CI 95% 1.04&ndash;1.07, p &lt; 0.001) and the HOMA-IR (OR = 1.156, CI 95% 1.08&ndash;1.23, p &lt; 0.001). Conclusions: Our study demonstrated that the TyG index, an efficient and cost-effective marker of insulin resistance, is associated with the variability of early post-challenge glucose levels and is an independent marker of being NGT-1h-high

Differential network analysis between sex of the genes related to comorbidities of type 2 mellitus diabetes

Abstract Background Some phenotypical changes may be related to changes in the associations among genes. The set of such associations is referred to as gene interaction (or association) networks. An association network represents the set of associations among genes in a given condition. Given two experimental conditions, Differential network analysis (DNA) algorithms analyse these differences by deriving a novel network representing the differences. Such algorithms receive as input experimental gene-expression data of two different conditions (e.g. healthy vs. diseased), then they derive experimental networks of associations among genes and, finally, they analyse differences among networks using statistical approaches. We explore the possibility to study possible rewiring due to sex factors, differently from classical approaches. Methods We apply DNA methods to evidence possible sex based differences on genes responsible for comorbidities of type 2 diabetes mellitus. Results Our analysis evidences the presence of differential networks in tissues that may explain the difference in the insurgence of comorbidities between males and females. Conclusion Main contributions of this work are (1) the definition of a novel framework of analysis able to shed light on the differences between males and females; (2) the identification of differential networks related to diabetes comorbidities

Metabolic syndrome and C reactive protein are associated with a reduced myocardial mechano-energetic efficiency

Context: Metabolic syndrome and elevated high sensitivity C-reactive protein (CRP) levels are associated with risk of cardiovascular diseases (CVD). A reduced myocardial mechano-energetic efficiency (MEE) has been found to be an independent predictor of CVD. Objective: To evaluate the association between metabolic syndrome and hsCRP levels with impaired MEE. Methods: Myocardial MEE was assessed by a validated echocardiography-derived measure in 1975 non-diabetic and prediabetic individuals subdivided into two groups according to the presence of metabolic syndrome. Results: Individuals with metabolic syndrome exhibited increased stroke work and myocardial oxygen consumption estimated by rate pressure product, and a reduced MEE per gram of LV mass (MEEi) as compared to subjects without metabolic syndrome, after adjusting for age, and sex. Myocardial MEEi progressively decreased in parallel with the increase of the number of metabolic syndrome components. In a multivariable regression analysis, both metabolic syndrome and hsCRP contributed to reduced myocardial MEEi independently of sex, total cholesterol, HDL, triglycerides, fasting and 2-h post-load glucose levels. When the study population was divided into 4 groups by the presence or absence of metabolic syndrome and by hsCRP levels above and below 3 mg/L, hsCRP levels ≥3 mg/L were associated with reduced myocardial MEEi both in subjects with metabolic syndrome and in those without the syndrome. Conclusion: Non-diabetic and prediabetic individuals with metabolic syndrome exhibit increased stroke work and myocardial oxygen consumption, and an impaired MEEi, an established predictor of adverse cardiovascular events, and elevated hsCRP levels in combination with metabolic syndrome aggravates the myocardial MEEi impairment

Effects of Alpha-2-HS-glycoprotein on cognitive and emotional assessment in prediabetic and diabetic subjects

Background High concentrations of Alpha-2-HS-glycoprotein, also called Fetuin-A (Fet-A), are associated with insulin resistance, obesity, non-alcoholic fatty liver disease, type 2 diabetes and polycystic ovary syndrome. Moreover, Fet-A is able to cross the bloodbrain barrier into ischemic brain tissue in adult humans. Although the brain is an important target of insulin action, there is little evidence associating serum levels of Fet-A with psychiatric conditions such as depression and cognitive decline, and no reports about the presence and degree of anxiety disorders. Methods We have examined cognitive and emotional alterations in a Caucasian population of 94 subjects. Results Our data confirmed that, irrespective of insulin sensitivity status, circulating Fet-A levels are positively associated with an increased risk of showing signs of depression according to the BDI-II test, and have reported new evidences of a positive association between Fet-A and state- and trait- anxiety, as measured by the STAI questionnaires. In contrast, no association was observed between Fet-A levels and cognitive performance on the MMSE. Limitations Although the study includes a well-characterized population, the small sample size and cross sectional nature are important limitations, and this results should not be considered definitive. The data are based only on Caucasian subjects and their generalizability to other ethnic groups should be done with caution. Conclusion Overall, these data suggest for the first time a role of Fet-A as an independent risk factor in the development of symptoms of anxiety and depression in prediabetic and diabetic subjects