Glycaemic Control in People with Type 2 Diabetes Mellitus Switching from Basal Insulin to Insulin Glargine 300 U/ml (Gla-300): Results from the REALI Pooled Database

INTRODUCTION: Using pooled data from the REALI European database, we evaluated the impact of previous basal insulin (BI) type on real-life effectiveness and safety of switching to insulin glargine 300 U/ml (Gla-300) in people with suboptimally controlled type 2 diabetes. METHODS: Patient-level data were pooled from 11 prospective, open-label, 24-week studies. Participants were classified according to the type of prior BI. Of the 4463 participants, 1282 (28.7%) were pre-treated with neutral protamine Hagedorn (NPH) insulin and 2899 (65.0%) with BI analogues (BIAs), and 282 (6.3%) had undetermined prior BI. RESULTS: There were no meaningful differences in baseline characteristics between subgroups, except for a higher prevalence of diabetic neuropathy in the NPH subgroup (21.6% versus 7.8% with BIAs). Mean ± standard deviation haemoglobin A1c (HbA1c) decreased from 8.73 ± 1.15% and 8.35 ± 0.95% at baseline to 7.71 ± 1.09% and 7.82 ± 1.06% at week 24 in the NPH and BIA subgroups, respectively. Least squares (LS) mean change in HbA1c was - 0.85% (95% confidence interval - 0.94 to - 0.77) in NPH subgroup and - 0.70% (- 0.77 to - 0.64) in BIA subgroup, with a LS mean absolute difference between subgroups of 0.16 (0.06-0.26; p = 0.002). Gla-300 mean daily dose was slightly increased at week 24 by 0.07 U/kg/day (approximately 6 U/day) in both subgroups. Incidences of symptomatic and severe hypoglycaemia were low, without body weight change. CONCLUSIONS: Irrespective of previous BI therapy (NPH insulin or BIAs), switching to Gla-300 improved glycaemic control without weight gain and with low symptomatic and severe hypoglycaemia incidences. However, a slightly greater glucose-lowering effectiveness was observed in people pre-treated with NPH insulin

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

Glucose tolerance stages in Cystic Fibrosis are idenfied by a unique pattern of defects of Beta-cell function

To assess the order of severity of the defects of three direct determinants of glucose regulation, i.e., beta-cell function, insulin clearance and insulin sensitivity, in patients with CF categorized according their glucose tolerance status, including early elevation of mid-OGTT glucose values (>140 and < 200 mg/dL), named AGT140

Le urolitine del metabotipo ‘A’ potenziano il profilo antinfiammatorio dei macrofagi M2

Background. Gli ellagitannini (ET), polifenoli presenti nel melograno, una volta ingeriti vengono metabolizzati dal microbiota intestinale a urolitine (Uro), a cui si ascrivono proprietà antinfiammatorie e antiossidanti nell’aterosclerosi. In relazione ai tipi di Uro prodotte, si distinguono due metabotipi, A (Uro A) e B (Uro A, IsoUro A, Uro B e Uro C). I macrofagi sono cellule chiave nell’infiammazione e nell’aterosclerosi, e, pertanto, eccellenti candidati come bersagli dell’azione delle urolitine. Scopo. Valutare l’effetto di dosi fisiologiche di Uro, che mimano i metabotipi, sul trascrittoma di macrofagi umani. Metodi. I monociti sono stati isolati da buffy coat di donatori sani e stimolati per indurre la polarizzazione M1 o M2, in presenza o in assenza di differenti combinazioni di Uro, corrispondenti ai metabotipi A e B. Le alterazioni a livello di trascrittoma sono state rilevate mediante tecnica microarray a genoma intero. Risultati. Il trascrittoma dei macrofagi M1 è stato solo minimamente influenzato dai metabotipi. Al contrario, le Uro del metabotipo A, modificano profondamente l’impronta trascrittomica degli M2, smorzando i processi di adesione focale e di migrazione transendoteliale e amplificando i meccanismi antisenescenza, mediante l’espressione dei geni implicati nell’attività lisosomiale e delle vie di riparazione del DNA. Nel metabotipo B, le modifiche del trascrittoma degli M2 sono molto contenute, e includono la repressione della via del segnale associata alla diapedesi. Conclusioni. Questi dati suggeriscono che le Uro del metabotipo A sono eccellenti candidate al ruolo di sostanze naturali a effetto netto antiaterogenico, attraverso l’esaltazione del ruolo antinfiammatorio dei macrofagi M2. Un ruolo analogo, ma quantitativamente molto minore, potrebbe essere svolto anche dalle urolitine del metabotipo B. Studio finanziato dal MIUR, Programma SIR2014 (RBSI14LHMB)

Claimed Effects, Outcome Variables and Methods of Measurement for Health Claims on Foods Related to Vision Proposed Under Regulation (EC) 1924/2006

Adequate visual function has a strong impact on the quality of life of people. Several foods and food components have been hypothesized to play a role in the maintenance of normal visual function and in the prevention of eye diseases. Some of these foods/food components have been the object of a request of authorization for use of health claims under Articles 13(5) or 14 of the Regulation (EC) 1924/2006. Most of these requests have received a negative opinion from the European Food Safety Authority (EFSA) due to the choice of inappropriate outcome variables (OVs) and/or methods of measurement (MMs) applied in the studies used to substantiate the claims. This manuscript refers to the collection, collation and critical analysis of OVs and MMs related to vision. Guidance document and requests for authorization of health claims were used to collect OVs and MMs related to vision. A literature review was performed to critically analyse OVs and MMs, with the aim of defining their appropriateness in the context of a specific claimed effect related to vision. The results highlight the importance of adequate choices of OVs and MMs for an effective substantiation of claims related to visual function

Claimed Effects, Outcome Variables and Methods of Measurement for Health Claims on Foods Related to Vision Proposed Under Regulation (EC) 1924/2006

Adequate visual function has a strong impact on the quality of life of people. Several foods and food components have been hypothesized to play a role in the maintenance of normal visual function and in the prevention of eye diseases. Some of these foods/food components have been the object of a request of authorization for use of health claims under Articles 13(5) or 14 of the Regulation (EC) 1924/2006. Most of these requests have received a negative opinion from the European Food Safety Authority (EFSA) due to the choice of inappropriate outcome variables (OVs) and/or methods of measurement (MMs) applied in the studies used to substantiate the claims. This manuscript refers to the collection, collation and critical analysis of OVs and MMs related to vision. Guidance document and requests for authorization of health claims were used to collect OVs and MMs related to vision. A literature review was performed to critically analyse OVs and MMs, with the aim of defining their appropriateness in the context of a specific claimed effect related to vision. The results highlight the importance of adequate choices of OVs and MMs for an effective substantiation of claims related to visual function

CACNA1E Variants Affect Beta Cell Function in Patients with Newly Diagnosed Type 2 Diabetes. The Verona Newly Diagnosed Type 2 Diabetes Study (VNDS) 3

Background: Genetic variability of the major subunit (CACNA1E) of the voltage-dependent Ca 2+ channel Ca V2.3 is associated to risk of type 2 diabetes, insulin resistance and impaired insulin secretion in nondiabetic subjects. The aim of the study was to test whether CACNA1E common variability affects beta cell function and/or insulin sensitivity in patients with newly diagnosed type 2 diabetes. Methodology/Principal Findings: In 595 GAD-negative, drug naïve patients (mean6SD; age: 58.5610.2 yrs; BMI: 29.965 kg/m 2, HbA1c: 7.061.3) with newly diagnosed type 2 diabetes we: 1. genotyped 10 tag SNPs in CACNA1E region reportedly covering,93 % of CACNA1E common variability: rs558994, rs679931, rs2184945, rs10797728, rs3905011, rs12071300, rs175338, rs3753737, rs2253388 and rs4652679; 2. assessed clinical phenotypes, insulin sensitivity by the euglycemic insulin clamp and beta cell function by state-of-art modelling of glucose/C-peptide curves during OGTT. Five CACNA1E tag SNPs (rs10797728, rs175338, rs2184945, rs3905011 and rs4652679) were associated with specific aspects of beta cell function (p,0.0520.01). Both major alleles of rs2184945 and rs3905011 were each (p,0.01 and p,0.005, respectively) associated to reduced proportional control with a demonstrable additive effect (p,0.005). In contrast, only the major allele of rs2253388 was related weakly to more severe insulin resistance (p,0.05). Conclusions/Significance: In patients with newly diagnosed type 2 diabetes CACNA1E common variability is strongl

Consistent findings in glycaemic control, body weight and hypoglycaemia with iGlarLixi (insulin glargine/lixisenatide titratable fixed-ratio combination) vs insulin glargine across baseline HbA1c, BMI and diabetes duration categories in the LixiLan-L trial

IGTPAims: To assess the impact of baseline characteristics on clinical outcomes in the LixiLan-L trial, a randomized open-label trial designed to evaluate the efficacy and safety of iGlarLixi, a novel fixed-ratio combination of insulin glargine 100 U (iGlar) plus lixisenatide, in comparison with iGlar over 30 weeks in a population of patients with type 2 diabetes mellitus (T2DM) inadequately controlled on a previous regimen of basal insulin alone or in combination with 1 or 2 oral glucose-lowering drugs. Materials and Methods: In this exploratory analysis of LixiLan-L (N = 736), efficacy outcomes were assessed within population subgroups derived from the following baseline characteristics: glycated haemoglobin [HbA1c; <8%, ≥8% (<64, ≥64 mmol/mol)]; duration of T2DM (<10, ≥10 years); body mass index (<30, ≥30 kg/m2). Furthermore, the incidence of symptomatic hypoglycaemia with plasma glucose ≤3.9 mmol/L (≤70 mg/dL) was also analysed according to the same subgroups. Results: Compared with the iGlar treatment group, patients treated with iGlarLixi showed consistently greater reductions in HbA1c during the treatment period, with higher percentages of patients achieving the HbA1c target level of <7% (<53 mmol/mol) in all of the subpopulations tested (P < .0001 for all), having consistent mitigation of body weight gain and with no major differences in the incidence of hypoglycaemia. Conclusions: iGlarLixi consistently improved glycaemic control compared with iGlar in all baseline characteristic subgroups of patients with T2DM inadequately controlled with insulin, including difficult-to-treat subgroups of patients with long duration of diabetes, obesity and high HbA1c. Clinical trial number: NCT02058160 (clinicaltrials.gov)