Publications by authors named "Riccardo C Bonadonna"

78 Publications

Glomerular filtration rate decline in T2DM following diagnosis. The Verona newly diagnosed diabetes study-12.

Diabetes Res Clin Pract 2021 Mar 22;175:108778. Epub 2021 Mar 22.

Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Hospital Trust of Verona, Verona, Italy.

Aims: Nephropathy is a complication of type 2 diabetes, with increased albuminuria and reduced glomerular filtration rate (GFR) as biomarkers. Rates of progression to end-stage-renal disease are variable among patients. In this study we have examined the GFR decline in newly diagnosed T2DM.

Methods: A cohort of 410 patients with newly diagnosed T2DM and with at least four serum creatinine during the follow-up period were recruited. A linear model was used to calculate the decline in eGFR. A multivariable logistic model was used to identify independent predictors of rapid eGFR decline.

Results: Average follow-up was 12.4 years. The eGFR change was -0.80 ± 2.23 ml/min/1.73 m per year. Patients were arbitrarily stratified into rapid decliners (≤-3.0 ml/min/1.73 m per year), moderate decliners (-2.9/-1 ml/min/1.73 m per year) and slow/no decliners (>-1.0 ml/min/1.73 m per year). Subjects in the 3 categories were 11.4%, 27.3%, and 61.3%, respectively. Albuminuria was the stronger predictor of rapid eGFR decline.

Conclusions: A rapid decline in eGFR occurs in approximately 1 out of 10 newly diagnosed subjects. This rapid decline can be predicted by widely accessible clinical features, such as albuminuria. Identification of rapid decliners may help to reduce progression toward advanced stages of nephropathy.
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http://dx.doi.org/10.1016/j.diabres.2021.108778DOI Listing
March 2021

Ethnic differences in beta cell function occur independently of insulin sensitivity and pancreatic fat in black and white men.

BMJ Open Diabetes Res Care 2021 Mar;9(1)

Diabetes and Nutritional Sciences Division, Faculty of Life Sciences and Medicine, King's College London, London, UK.

Introduction: It is increasingly recognized that type 2 diabetes (T2D) is a heterogenous disease with ethnic variations. Differences in insulin secretion, insulin resistance and ectopic fat are thought to contribute to these variations. Therefore, we aimed to compare postprandial insulin secretion and the relationships between insulin secretion, insulin sensitivity and pancreatic fat in men of black West African (BA) and white European (WE) ancestry.

Research Design And Methods: A cross-sectional, observational study in which 23 WE and 23 BA men with normal glucose tolerance, matched for body mass index, underwent a mixed meal tolerance test with C peptide modeling to measure beta cell insulin secretion, an MRI to quantify intrapancreatic lipid (IPL), and a hyperinsulinemic-euglycemic clamp to measure whole-body insulin sensitivity.

Results: Postprandial insulin secretion was lower in BA versus WE men following adjustment for insulin sensitivity (estimated marginal means, BA vs WE: 40.5 (95% CI 31.8 to 49.2) × 10 vs 56.4 (95% CI 48.9 to 63.8) × 10 pmol/m body surface area × 180 min, p=0.008). There was a significantly different relationship by ethnicity between IPL and insulin secretion, with a stronger relationship in WE than in BA (r=0.59 vs r=0.39, interaction p=0.036); however, IPL was not a predictor of insulin secretion in either ethnic group following adjustment for insulin sensitivity.

Conclusions: Ethnicity is an independent determinant of beta cell function in black and white men. In response to a meal, healthy BA men exhibit lower insulin secretion compared with their WE counterparts for their given insulin sensitivity. Ethnic differences in beta cell function may contribute to the greater risk of T2D in populations of African ancestry.
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http://dx.doi.org/10.1136/bmjdrc-2020-002034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993168PMC
March 2021

Glycaemic Control with Insulin Glargine 300 U/mL in Individuals with Type 2 Diabetes and Chronic Kidney Disease: A REALI European Pooled Data Analysis.

Diabetes Ther 2021 Apr 9;12(4):1159-1174. Epub 2021 Mar 9.

Department of Medicine I, University Hospital Aachen, Aachen, Germany.

Introduction: Management of type 2 diabetes mellitus (T2DM) in patients with chronic kidney disease is complex. Using the REALI European pooled database, we determined the impact of baseline renal function on the effectiveness and safety of insulin glargine 300 U/mL (Gla-300) initiated in adults with inadequately controlled T2DM.

Methods: Data from 1712 patients with available estimated glomerular filtration rate (eGFR) at baseline were pooled from six 24-week prospective studies. Patients who received once-daily subcutaneous injections of Gla-300 were classified into four renal function subgroups, according to baseline eGFR: ≥ 90 (N = 599), 60-89 (N = 786), 45-59 (N = 219), and 15-44 mL/min/1.73 m (N = 108).

Results: Compared to those with baseline eGFR ≥ 60 mL/min/1.73 m, patients with lower eGFR values tended to be older, had a longer T2DM duration, and were more likely to present diabetic complications. After 24 weeks of Gla-300 therapy, the least-squares mean (95% confidence interval) decrease in haemoglobin A1c (HbA1c) from baseline (- 1.14% [- 1.28 to - 1.00], - 1.21% [- 1.34 to - 1.08], - 1.19% [- 1.36 to - 1.01], and - 0.99% [- 1.22 to - 0.76]) and the proportion of patients achieving HbA1c < 7.5% (53.3%, 51.3%, 49.5%, and 51.5%) were comparable in the ≥ 90, 60-89, 45-59, and 15-44 mL/min/1.73 m subgroups, respectively. Although the incidence of hypoglycaemia was overall low, more patients in the eGFR 15-44 mL/min/1.73 m subgroup experienced hypoglycaemia at night or at any time of the day compared with higher eGFR subgroups. There were no notable differences between the renal function subgroups in the changes in Gla-300 daily dose and body weight from baseline to week 24.

Conclusion: Although an eGFR of 15-44 mL/min/1.73 m was associated with a slightly increased risk of hypoglycaemia among patients with inadequately controlled T2DM, Gla-300 provided glycaemic improvement with an overall favourable safety profile regardless of baseline eGFR.
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http://dx.doi.org/10.1007/s13300-021-01031-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994474PMC
April 2021

Feasibility of a scale-down production of [68Ga]Ga-NODAGA-Exendin-4 in a hospital based radiopharmacy.

Curr Radiopharm 2021 Mar 9. Epub 2021 Mar 9.

Nuclear Medicine and Molecular Imaging Department, University Hospital of Parma, via Gramsci 14, 43126 Parma. Italy.

Background: Glucagon-like peptide 1 receptor (GLP-1R) is preferentially expressed in β-cells, but it is highly expressed in human insulinomas and gastrinomas. Several GLP-1 receptor-avid radioligands have been developed to image insulin-secreting tumors or to provide a quantitative in vivo biomarker of pancreatic β-cell mass. Exendin-4 is a high affinity ligand of the GLP1-R, which is a candidate for being labeled with a PET isotope and used for imaging purposes.

Objective: Here, we report the development and validation results of a semi manual procedure to label [Lys40,Nle14(Ahx-NODAGA)NH2]exendin-4, with Ga-68.

Methods: A Ge/Ga Generator (GalliaPharma®,Eckert and Ziegler) was eluted with 0.1M HCl on an automated synthesis module (Scintomics GRP®). The peptide contained in the kit vial (Radioisotope Center POLATOM) in different amounts (10-20-30 µg) was reconstituted with 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethansulfonic acid (HEPES) solution and 68GaCl3 (400-900 MBq), followed by 10 min incubation at 95°C. The reaction solution was then purified through an Oasis HLB column. The radiopharmaceutical product was tested for quality controls (CQs), in accordance with the European Pharmacopoeia standards.

Results: The synthesis of Ga]Ga-NODAGA-Exendin-4 provided optimal results with 10 µg of peptide, getting the best radiochemical yield (23.53 ± 2.4 %), molar activity (100 GBq/µmol) and radiochemical purity (91.69 %).

Conclusion: The study developed an imaging tool [Ga]Ga-NODAGA-Exendin-4, avoiding pharmacological effects of exendin-4, for the clinical community.
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http://dx.doi.org/10.2174/1874471014666210309151930DOI Listing
March 2021

Impact of Age on the Effectiveness and Safety of Insulin Glargine 300 U/mL: Results from the REALI European Pooled Data Analysis.

Diabetes Ther 2021 Apr 1;12(4):1073-1097. Epub 2021 Mar 1.

Endocrinology, Diabetology and Nutrition Department, Toulouse University Hospital, Toulouse, France.

Introduction: Patients aged ≥ 65 years continue to be underrepresented in clinical studies related to type 2 diabetes mellitus (T2DM). Accordingly, the REALI pooled analysis was performed to evaluate the effectiveness and safety of insulin glargine 300 U/mL (Gla-300) across different age subgroups, using data from 14 interventional and non-interventional studies.

Methods: Pooled efficacy and safety data were collected from 8106 European patients with uncontrolled T2DM who were initiated on or switched to Gla-300 injected once daily for 24 weeks. Patients were categorised into five age subgroups: < 50 (N = 727), 50-59 (N = 2030), 60-69 (N = 3054), 70-79 (N = 1847) and ≥ 80 years (N = 448).

Results: Mean baseline haemoglobin A1c (HbA1c) decreased linearly from the youngest (9.10%) to the oldest (8.46%) age subgroup. Following Gla-300 initiation, there were similar HbA1c reductions across age groups, with a least squares mean (95% confidence interval) change in HbA1c from baseline to week 24 of - 1.09% (- 1.18 to - 1.00), - 1.08% (- 1.14 to - 1.03), - 1.12% (- 1.17 to - 1.07), - 1.18% (- 1.24 to - 1.12) and - 1.11% (- 1.23 to - 0.99) in the < 50, 50-59, 60-69, 70-79 and ≥ 80 years subgroups, respectively. The incidences and event rates of reported hypoglycaemia were overall low. Compared to younger age subgroups, lower incidences of symptomatic hypoglycaemia occurring at any time of the day (5.9 vs. 7.6-9.4% for the younger subgroups) or during the night (0.5 vs. 1.6-2.5%) were recorded in patients aged ≥ 80 years. By contrast, the highest incidence of severe hypoglycaemia occurring any time of the day was reported in the subgroup aged ≥ 80 years (1.1 vs. 0.1-0.6% for the younger age subgroups).

Conclusion: Gla-300 initiated in patients with uncontrolled T2DM provides glycaemic improvement with a favourable safety profile across a wide range of ages.
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http://dx.doi.org/10.1007/s13300-021-01030-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994463PMC
April 2021

Glucose Tolerance Stages in Cystic Fibrosis Are Identified by a Unique Pattern of Defects of Beta-Cell Function.

J Clin Endocrinol Metab 2021 Mar;106(4):e1793-e1802

Pediatric Diabetes and Metabolic Disorders Unit, Regional Center for Pediatric Diabetes, University Hospital of Verona, Verona, Italy.

Objective: We aimed to assess the order of severity of the defects of 3 direct determinants of glucose regulation-beta-cell function, insulin clearance, and insulin sensitivity-in patients with cystic fibrosis (CF), categorized according their glucose tolerance status, including early elevation of mid-level oral glucose tolerance test (OGTT) glucose values (>140 and <200 mg/dL), referred to as AGT140.

Methods: A total of 232 CF patients aged 10 to 25 years underwent OGTT. Beta-cell function and insulin clearance were estimated by OGTT mathematical modeling and OGTT-derived biomarkers of insulin secretion and sensitivity were calculated. The association between glucometabolic variables and 5 glucose tolerance stages (normal glucose tolerance [NGT], AGT140, indeterminate glucose tolerance [INDET], impaired glucose tolerance [IGT], cystic fibrosis-related diabetes CFRD]) was assessed with a general linear model.

Results: Beta-cell function and insulin sensitivity progressively worsened across glucose tolerance stages (P < 0.001), with AGT140 patients significantly differing from NGT (all P < 0.01). AGT140 and INDET showed a degree of beta-cell dysfunction similar to IGT and CFRD, respectively (all P < 0.01). Insulin clearance was not significantly associated with glucose tolerance stages (P = 0.162). Each stage of glucose tolerance was uniquely identified by a specific combination of defects of the direct determinants of glucose regulation.

Conclusions: In CF patients, each of the 5 glucose tolerance stages shows a unique pattern of defects of the direct determinants of glucose regulation, with AGT140 patients significantly differing from NGT and being similar to IGT. These findings suggest that AGT140 should be recognized as a distinct glucose tolerance stage and that reconsideration of the grade of glucometabolic deterioration across glucose tolerance stages in CF is warranted.
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http://dx.doi.org/10.1210/clinem/dgaa932DOI Listing
March 2021

Changes induced by metabolic surgery on the main components of glucose/insulin system in patients with diabetes and obesity.

Acta Diabetol 2021 Apr 24;58(4):513-516. Epub 2020 Nov 24.

Section of Endocrinology, Diabetes and Metabolism, University and Azienda Ospedaliera Universitaria Integrata of Verona, Piazzale Stefani, 1, 37126, Verona, Italy.

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http://dx.doi.org/10.1007/s00592-020-01633-2DOI Listing
April 2021

Chronic complications in patients with newly diagnosed type 2 diabetes: prevalence and related metabolic and clinical features: the Verona Newly Diagnosed Type 2 Diabetes Study (VNDS) 9.

BMJ Open Diabetes Res Care 2020 08;8(1)

Department of Medicine and Surgery, University of Parma, Parma, Italy.

Introduction: We explored the presence of chronic complications in subjects with newly diagnosed type 2 diabetes referred to the Verona Diabetes Clinic. Metabolic (insulin secretion and sensitivity) and clinical features associated with complications were also investigated.

Research Design And Methods: The comprehensive assessment of microvascular and macrovascular complications included detailed medical history, resting ECG, ultrasonography of carotid and lower limb arteries, quantitative neurological evaluation, cardiovascular autonomic tests, ophthalmoscopy, kidney function tests. Insulin sensitivity and beta-cell function were assessed by state-of-the-art techniques (insulin clamp and mathematical modeling of glucose/C-peptide curves during oral glucose tolerance test).

Results: We examined 806 patients (median age years, two-thirds males), of whom prior clinical cardiovascular disease (CVD) was revealed in 11.2% and preclinical CVD in 7.7%. Somatic neuropathy was found in 21.2% and cardiovascular autonomic neuropathy in 18.6%. Retinopathy was observed in 4.9% (background 4.2%, proliferative 0.7%). Chronic kidney disease (estimated glomerular filtration rate <60 mL/min/1.73 m) was found in 8.8% and excessive albuminuria in 13.2% (microalbuminuria 11.9%, macroalbuminuria 1.3%).Isolated microvascular disease occurred in 30.8%, isolated macrovascular disease in 9.3%, a combination of both in 9.1%, any complication in 49.2% and no complications in 50.8%.Gender, age, body mass index, smoking, hemoglobin A1c and/or hypertension were independently associated with one or more complications. Insulin resistance and beta-cell dysfunction were associated with macrovascular but not microvascular disease.

Conclusions: Despite a generally earlier diagnosis for an increased awareness of the disease, as many as ~50% of patients with newly diagnosed type 2 diabetes had clinical or preclinical manifestations of microvascular and/or macrovascular disease. Insulin resistance might play an independent role in macrovascular disease.

Trial Registration Number: NCT01526720.
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http://dx.doi.org/10.1136/bmjdrc-2020-001549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443259PMC
August 2020

Insulin clearance as the major player in the hyperinsulinaemia of black African men without diabetes.

Diabetes Obes Metab 2020 10 1;22(10):1808-1817. Epub 2020 Jul 1.

Department of Diabetes, School of Life Course Sciences, Faculty of Life Sciences & Medicine, King's College London, London, UK.

Aim: To investigate relationships between insulin clearance, insulin secretion, hepatic fat accumulation and insulin sensitivity in black African (BA) and white European (WE) men.

Methods: Twenty-three BA and twenty-three WE men with normal glucose tolerance, matched for age and body mass index, underwent a hyperglycaemic clamp to measure insulin secretion and clearance, hyperinsulinaemic-euglycaemic clamp with stable glucose isotope infusion to measure whole-body and hepatic-specific insulin sensitivity, and magnetic resonance imaging to quantify intrahepatic lipid (IHL).

Results: BA men had higher glucose-stimulated peripheral insulin levels (48.1 [35.5, 65.2] × 10 vs. 29.9 [23.3, 38.4] × 10 pmol L  × min, P = .017) and lower endogeneous insulin clearance (771.6 [227.8] vs. 1381 [534.3] mL m body surface area min , P < .001) compared with WE men. There were no ethnic differences in beta-cell insulin secretion or beta-cell responsivity to glucose, even after adjustment for prevailing insulin sensitivity. In WE men, endogenous insulin clearance was correlated with whole-body insulin sensitivity (r = 0.691, P = .001) and inversely correlated with IHL (r = -0.674, P = .001). These associations were not found in BA men.

Conclusions: While normally glucose-tolerant BA men have similar insulin secretory responses to their WE counterparts, they have markedly lower insulin clearance, which does not appear to be explained by either insulin resistance or hepatic fat accumulation. Low insulin clearance may be the primary mechanism of hyperinsulinaemia in populations of African origin.
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http://dx.doi.org/10.1111/dom.14101DOI Listing
October 2020

A performance score of the quality of inpatient diabetes care is a marker of clinical outcomes and suggests a cause-effect relationship between hypoglycaemia and the risk of in-hospital mortality.

Diabetes Metab Res Rev 2020 11 25;36(8):e3347. Epub 2020 Jun 25.

Department of Medicine and Surgery, Università di Parma, Parma, Italy.

Aims: To build a tool to assess the management of inpatients with diabetes mellitus and to investigate its relationship, if any, with clinical outcomes.

Materials And Methods: A total of 678 patients from different settings, Internal Medicine (IMU, n = 255), General Surgery (GSU, n = 230) and Intensive Care (ICU, n = 193) Units, were enrolled. A work-flow of clinical care of diabetes was created according to guidelines. The workflow was divided into five different domains: (a) initial assessment; (b) glucose monitoring; (c) medical therapy; (d) consultancies; (e) discharge. Each domain was assessed by a performance score (PS), computed as the sum of the scores achieved in a set of indicators of clinical appropriateness, management and patient empowerment. Appropriate glucose goals were included as intermediate phenotypes. Clinical outcomes included: hypoglycaemia, survival rate and clinical conditions at discharge.

Results: The total PS and those of initial assessment and glucose monitoring were significantly lower in GSU with respect to IMU and ICU (P < .0001). The glucose monitoring PS was associated with lower risk of hypoglycaemia (OR = 0.55; P < .0001), whereas both the PSs of glucose monitoring and medical therapy resulted associated with higher in-hospital survival only in the IMU ward (OR = 6.67 P = .001 and OR = 2.38 P = .03, respectively). Instrumental variable analysis with the aid of PS of glucose monitoring showed that hypoglycaemia may play a causal role in in-hospital mortality (P = .04).

Conclusions: The quality of in-hospital care of diabetes may affect patient outcomes, including glucose control and the risk of hypoglycaemia, and through the latter it may influence the risk of in-hospital mortality.
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http://dx.doi.org/10.1002/dmrr.3347DOI Listing
November 2020

Rationale and methodology for a European pooled analysis of postmarketing interventional and observational studies of insulin glargine 300 U/mL in diabetes: protocol of REALI project.

BMJ Open 2020 04 28;10(4):e033659. Epub 2020 Apr 28.

Global Diabetes, Sanofi SA, Paris, Île-de-France, France.

Introduction: Type 2 diabetes mellitus (T2DM) is a common and heterogeneous disease. Using advanced analytic approaches to explore real-world data may identify different disease characteristics, responses to treatment and progression patterns. Insulin glargine 300 units/mL (Gla-300) is a second-generation basal insulin analogue with preserved glucose-lowering efficacy but reduced risk of hypoglycaemia. The purpose of the REALI pooled analysis described in this paper is to advance the understanding of the effectiveness and real-world safety of Gla-300 based on a large European patient database of postmarketing interventional and observational studies.

Methods And Analysis: In the current round of pooling, REALI will include data from up to 10 000 subjects with diabetes mellitus (mostly T2DM) from 20 European countries. Outcomes of interest include change from baseline to week 24 in haemoglobin A, fasting plasma glucose, self-measured plasma glucose, body weight, insulin dose, incidence and rate of any-time-of-the-day and nocturnal hypoglycaemia. The data pool is being investigated using two complementary methodologies: a conventional descriptive, univariate and multivariable prognostic analysis; and a data-mining approach using subgroup discovery to identify phenotypic clusters of patients who are highly associated with the outcome of interest. By mid-2019, deidentified data of 7584 patients were included in the REALI database, with a further expected increase in patient number in 2020 as a result of pooling additional studies.

Ethics And Dissemination: The proposed study does not involve collection of primary data. Moreover, all individual study protocols were approved by independent local ethics committees, and all study participants provided written informed consent. Furthermore, patient data is deidentified before inclusion in the REALI database. Hence, there is no requirement for ethical approval. Results will be disseminated via peer-reviewed publications and presentations at international congresses as data are analysed.
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http://dx.doi.org/10.1136/bmjopen-2019-033659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213840PMC
April 2020

Sodium-glucose cotransporter 2 inhibitors antagonize lipotoxicity in human myeloid angiogenic cells and ADP-dependent activation in human platelets: potential relevance to prevention of cardiovascular events.

Cardiovasc Diabetol 2020 04 7;19(1):46. Epub 2020 Apr 7.

Endocrinology and Metabolism, Department of Medicine and Surgery, University of Parma, Parma, Italy.

Background: The clear evidence of cardiovascular benefits in cardiovascular outcome trials of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in type 2 diabetes might suggest an effect on atherosclerotic plaque vulnerability and/or thrombosis, in which myeloid angiogenic cells (MAC) and platelets (PLT) are implicated. We tested the effects of SGLT2i on inflammation and oxidant stress in a model of stearic acid (SA)-induced lipotoxicity in MAC and on PLT activation. The possible involvement of the Na/H exchanger (NHE) was also explored.

Method: MAC and PLT were isolated from peripheral blood of healthy subjects and incubated with/without SGLT2i [empagliflozin (EMPA) and dapagliflozin (DAPA) 1-100 μM] to assess their effects on SA (100 μM)-induced readouts of inflammation, oxidant stress and apoptosis in MAC and on expression of PLT activation markers by flow-cytometry after ADP-stimulation. Potential NHE involvement was tested with amiloride (aspecific NHE inhibitor) or cariporide (NHE1 inhibitor). Differences among culture conditions were identified using one-way ANOVA or Friedman test.

Results: NHE isoforms (1,5-9), but not SGLT2 expression, were expressed in MAC and PLT. EMPA and DAPA (100 μM) significantly reduced SA-induced inflammation (IL1β, TNFα, MCP1), oxidant stress (SOD2, TXN, HO1), but not apoptosis in MAC. EMPA and DAPA (both 1 μM) reduced PLT activation (CD62p and PAC1 expression). SGLT2i effects were mimicked by amiloride, and only partially by cariporide, in MAC, and by both inhibitors in PLT.

Conclusions: EMPA and DAPA ameliorated lipotoxic damage in stearate-treated MAC, and reduced ADP-stimulated PLT activation, potentially via NHE-inhibition, thereby pointing to plaque stabilization and/or thrombosis inhibition as potential mechanism(s) involved in SGLT2i-mediated cardiovascular protection.
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http://dx.doi.org/10.1186/s12933-020-01016-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140327PMC
April 2020

Comparable efficacy with similarly low risk of hypoglycaemia in patient- vs physician-managed basal insulin initiation and titration in insulin-naïve type 2 diabetic subjects: The Italian Titration Approach Study.

Diabetes Metab Res Rev 2020 09 5;36(6):e3304. Epub 2020 Apr 5.

Section of Endocrinology and Metabolism, Department of Medicine, Perugia University Medical School, Perugia, Italy.

Aims: People with uncontrolled type 2 diabetes (T2DM) often delay initiating and titrating basal insulin. Patient-managed titration may reduce such deferral. The Italian Titration Approach Study (ITAS) compared the efficacy and safety of insulin glargine 300 U/mL (Gla-300) initiation and titration using patient- (nurse-supported) or physician-management in insulin-naïve patients with uncontrolled T2DM.

Materials And Methods: ITAS was a multicentre, phase IV, 24-week, open-label, randomized (1:1), parallel-group study. Insulin-naïve adults with T2DM for ≥1 year with poor metabolic control initiated Gla-300 after discontinuation of SU/glinides, and were randomized to self-titrate insulin dose (nurse-assisted) or have it done by the physician. The primary endpoint was change in HbA . Secondary outcomes included hypoglycaemia incidence and rate, change in fasting self-monitored plasma glucose, patient-reported outcomes (PROs), and adverse events.

Results: Three hundred and fifty five participants were included in the intention-to-treat population. At Week 24, HbA reduction from baseline was non-inferior in patient- vs physician-managed arms [least squares mean (LSM) change (SE): -1.60% (0.06) vs -1.49% (0.06), respectively; LSM difference: -0.11% (95% CI: -0.26 to 0.04)]. The incidence and rates of hypoglycaemia were similarly low in both arms: relative risk of confirmed and/or severe nocturnal (00:00-05:59 hours) hypoglycaemia was 0.77 (95% CI: 0.27 to 2.18). No differences were observed for improvement in PROs. No safety concerns were reported.

Conclusions: In the T2DM insulin-naïve, SU/glinides discontinued population, patient-managed (nurse-assisted) titration of Gla-300 may be a suitable option as it provides improved glycaemic control with low risk of hypoglycaemia, similar to physician-managed titration.
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http://dx.doi.org/10.1002/dmrr.3304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540052PMC
September 2020

Loss of ZnT8 function protects against diabetes by enhanced insulin secretion.

Nat Genet 2019 11 1;51(11):1596-1606. Epub 2019 Nov 1.

Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, UK.

A rare loss-of-function allele p.Arg138* in SLC30A8 encoding the zinc transporter 8 (ZnT8), which is enriched in Western Finland, protects against type 2 diabetes (T2D). We recruited relatives of the identified carriers and showed that protection was associated with better insulin secretion due to enhanced glucose responsiveness and proinsulin conversion, particularly when compared with individuals matched for the genotype of a common T2D-risk allele in SLC30A8, p.Arg325. In genome-edited human induced pluripotent stem cell (iPSC)-derived β-like cells, we establish that the p.Arg138* allele results in reduced SLC30A8 expression due to haploinsufficiency. In human β cells, loss of SLC30A8 leads to increased glucose responsiveness and reduced K channel function similar to isolated islets from carriers of the T2D-protective allele p.Trp325. These data position ZnT8 as an appealing target for treatment aimed at maintaining insulin secretion capacity in T2D.
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http://dx.doi.org/10.1038/s41588-019-0513-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858874PMC
November 2019

Vitamin D affects insulin sensitivity and β-cell function in obese non-diabetic youths.

Eur J Endocrinol 2019 Oct;181(4):439-450

Pediatric Diabetes and Metabolic Disorders, Department of Surgical Sciences, Dentistry, Paediatrics and Gynaecology, University of Verona, Verona, Italy.

Objective: Vitamin D may potentially play a central role in glucose homeostasis and β-cell function (BCF), although studies are not consistent. Aim of our study was to test the hypotheses of a direct relationship between vitamin D, insulin sensitivity (IS) and BCF in overweight and obese non-diabetic children.

Design And Methods: Cross-sectional study carried out at the Childhood Obesity Outpatient Clinic, University Hospital of Verona. One hundred twenty-two Caucasian overweight and obese children (age: 12.8 ± 0.2 years) were enrolled. Exclusion criteria: genetic or endocrine causes of obesity, chronic diseases or therapies. Patients underwent oral glucose tolerance test. HOMA-IR, Matsuda index and insulinogenic index were calculated. BCF was reconstructed by mathematical modeling and described by Derivative and Proportional Control. Total 25-hydroxyvitamin D and vitamin D-binding protein (VDBP) were measured. Two SNPs (rs4588 and rs7041) in the VDBP gene were studied, and bioavailable vitamin D (BVD) was calculated.

Results: Hypovitaminosis D was documented in 90% of patients. Forty-seven subjects were homozygous for both SNPs. Total vitamin D was positively correlated with Matsuda index (P = 0.002), VDBP (P = 0.045), and negatively with BMI SDS (P = 0.043), HOMA-IR (P = 0.008), HOMA-B (P = 0.001), IGI (P = 0.007), derivative control (P = 0.036) and proportional control (P = 0.018). Total vitamin D, adjusted for age, gender, BMI SDS, puberty and seasonality of vitamin D measurement, was a predictor of Matsuda index, HOMA-IR, HOMA-B, IGI, proportional control (all P < 0.05). BVD was positively correlated with total vitamin D (P < 0.001) and negatively with BMI SDS (P = 0.041).

Conclusions: Hypovitaminosis D negatively influences BCF and IS, suggesting that vitamin D levels might be implicated in glucose metabolism impairment in overweight and obese individuals.
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http://dx.doi.org/10.1530/EJE-19-0369DOI Listing
October 2019

Ethnic differences in intrahepatic lipid and its association with hepatic insulin sensitivity and insulin clearance between men of black and white ethnicity with early type 2 diabetes.

Diabetes Obes Metab 2019 09 18;21(9):2163-2168. Epub 2019 Jun 18.

Department of Diabetes, School of Life Course Sciences, Faculty of Life Sciences & Medicine, King's College London, London, UK.

Intrahepatic lipid (IHL) is linked with reduced hepatic insulin sensitivity and insulin clearance. Despite their high risk for type 2 diabetes (T2D), there have been limited investigations of these relationships in black populations. We investigated these relationships in 18 white European (WE) and 18 black West African (BWA) men with T2D <5 years. They underwent magnetic resonance imaging to quantify IHL, a hyperinsulinemic euglycaemic clamp with [6,6 H ] glucose infusion to assess hepatic insulin sensitivity and a hyperglycaemic clamp to assess insulin clearance. BWA men had lower IHL than WE men (3.7 [5.3] vs 6.6 [10.6]%, P = 0.03). IHL was inversely associated with basal hepatic insulin sensitivity in WE but not BWA men (BWA: r = -0.01, P = 0.96; WE: r = -0.72, P = 0.006) with a significant interaction by ethnicity (P  = 0.05); however, IHL was not associated with % suppression of endogenous glucose production by insulin in either ethnicity. IHL showed a trend to an association with insulin clearance in BWA only (BWA: r = -0.42, P = 0.09; WE: r = -0.14, P = 0.58). The lack of association between IHL and hepatic insulin sensitivity in BWA men indicates IHL may play a lesser detrimental role in T2D in BWA men.
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http://dx.doi.org/10.1111/dom.13771DOI Listing
September 2019

Central role of the β-cell in driving regression of diabetes after liver transplantation in cirrhotic patients.

J Hepatol 2019 05 21;70(5):954-962. Epub 2019 Jan 21.

Diabetes Service, Endocrinology and Metabolic Diseases Unit, IRCCS "Cà Granda - Ospedale Maggiore Policlinico" Foundation, and Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy. Electronic address:

Background & Aims: Diabetes occurring as a direct consequence of loss of liver function is usually characterized by non-diabetic fasting plasma glucose (FPG) and haemoglobin A (HbA) levels and should regress after orthotopic liver transplantation (OLT). This observational, longitudinal study investigated the relationship between the time-courses of changes in all 3 direct determinants of glucose regulation, i.e., β-cell function, insulin clearance and insulin sensitivity, and diabetes regression after OLT.

Methods: Eighty cirrhotic patients with non-diabetic FPG and HbA levels underwent an extended oral glucose tolerance test (OGTT) before and 3, 6, 12 and 24 months after OLT. The OGTT data were analysed with a mathematical model to estimate derivative control (DC) and proportional control (PC) of β-cell function and insulin clearance (which determine insulin bioavailability), and with the Oral Glucose Insulin Sensitivity (OGIS)-2 h index to estimate insulin sensitivity.

Results: At baseline, 36 patients were diabetic (45%) and 44 were non-diabetic (55%). Over the 2-year follow-up, 23 diabetic patients (63.9%) regressed to non-diabetic glucose regulation, whereas 13 did not (36.1%); moreover, 4 non-diabetic individuals progressed to diabetes (9.1%), whereas 40 did not (90.9%). Both DC and PC increased in regressors (from month 3 and 24, respectively) and decreased in progressors, whereas they remained stable in non-regressors and only PC decreased in non-progressors. Insulin clearance increased in all groups, apart from progressors. Likewise, OGIS-2 h improved at month 3 in all groups, but thereafter it continued to improve only in regressors, whereas it returned to baseline values in the other groups.

Conclusions: Increased insulin bioavailability driven by improved β-cell function plays a central role in favouring diabetes regression after OLT, in the presence of a sustained improvement of insulin sensitivity.

Lay Summary: Diabetes occurring in cirrhosis as a direct consequence of loss of liver function should regress after transplantation of a new functioning liver, though the pathophysiological mechanisms are unclear. This is the first study evaluating the contribution of all 3 direct determinants of insulin-dependent glucose regulation using a sophisticated mathematical model. Results show that β-cell function is the key process governing favourable or detrimental changes in glucose regulation in cirrhotic patients undergoing transplantation, pointing to the need to develop therapies to sustain β-cell function in these individuals.

Trial Registration: ClinicalTrials.gov, NCT02038517.
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http://dx.doi.org/10.1016/j.jhep.2019.01.015DOI Listing
May 2019

Quantification of epicardial fat with cardiac CT angiography and association with cardiovascular risk factors in symptomatic patients: from the ALTER-BIO (Alternative Cardiovascular Bio-Imaging markers) registry.

Diagn Interv Radiol 2019 Jan;25(1):35-41

Cardiovascular Imaging Center SDN IRCCS, Naples, Italy.

Purpose: We aimed to assess the association between features of epicardial adipose tissue and demographic, morphometric and clinical data, in a large population of symptomatic patients with clinical indication to cardiac computed tomography (CT) angiography.

Methods: Epicardial fat volume (EFV) and adipose CT density of 1379 patients undergoing cardiac CT angiography (918 men, 66.6%; age range, 18-93 years; median age, 64 years) were semi-automatically quantified. Clinical variables were compared between diabetic and nondiabetic patients to assess potential differences in EFV and adipose CT density. Multiple regression models were calculated to find the clinical variables with a significant association with EFV and adipose CT density.

Results: The median EFV in diabetic patients (112.87 mL) was higher compared with nondiabetic patients (82.62 mL; P < 0.001). The explanatory model of the multivariable analysis showed the strongest associations between EFV and BMI (β=0.442) and age (β=0.365). Significant yet minor association was found with sex (β=0.203), arterial hypertension (β=0.072), active smoking (β=0.068), diabetes (β=0.068), hypercholesterolemia (β=0.046) and cardiac height (β=0.118). The mean density of epicardial adipose tissue was associated with BMI (β=0.384), age (β=0.105), smoking (β=0.088), and diabetes (β=0.085).

Conclusion: In a large population of symptomatic patients, EFV is higher in diabetic patients compared with nondiabetic patients. Clinical variables are associated with quantitative features of epicardial fat.
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http://dx.doi.org/10.5152/dir.2018.18037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6339622PMC
January 2019

"IGT-like" status in normoglucose tolerant obese children and adolescents: the additive role of glucose profile morphology and 2-hours glucose concentration during the oral glucose tolerance test.

Int J Obes (Lond) 2019 07 19;43(7):1363-1369. Epub 2018 Dec 19.

Pediatric Diabetes and Metabolic Disorders Unit, University Hospital of Verona, Verona, Italy.

Objective: To assess whether combining glucose shape and 2-h glucose concentration during an oral glucose tolerance test (OGTT) may help identifying normal glucose tolerant obese children/adolescents with an impaired glucose tolerant (IGT)-like metabolic profile in term of insulin sensitivity (Matsuda index) and β-cell function (disposition index: DI).

Subjects, Methods, And Main Outcome Measure: In total, 654 non-diabetic obese children/adolescents underwent a 2 h OGTT. The whole population was classified according to 2-hour plasma glucose ( < 100, 100-119, 120-139, 140-200 mg/dL) and glucose shape (monophasic or biphasic). Monophasic morphology was characterized by an increase in OGTT glucose concentration followed by a decline of at least 4.5 mg/dL, a biphasic response was defined as a decrease in glucose after an initial increase, followed by a second increase of ≥ 4.5 mg/dL. A subset of 69 participants had also a prolonged OGTT to estimate β-cell function in "biphasic" versus "monophasic" patients.

Results: Matsuda index and DI decreased across 2-h glucose categories (both p < 0.001) and were lower in monophasic compared with biphasic children, independently of 2-h glucose category (both p < 0.001, both p for glucose category×shape interaction > 0.05). Normal glucose tolerant children with 2-h glucose of 120-139 mg/dl and monophasic glucose shape did not differ from IGT children, as regards Matsuda index and DI (both p > 0.05). Among children undergoing a prolonged OGTT, those with a monophasic glucose shape had worse β-cell function, modeled as proportional control, than those with a biphasic shape (p = 0.031).

Conclusions: A monophasic OGTT glucose shape is associated with unfavorable glucose metabolism independently of 2-h glucose concentration. Children combining monophasic shape and normal-high 2-h glucose have an IGT-like glucose metabolism.
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http://dx.doi.org/10.1038/s41366-018-0297-5DOI Listing
July 2019

Thromboxane-Dependent Platelet Activation in Obese Subjects with Prediabetes or Early Type 2 Diabetes: Effects of Liraglutide- or Lifestyle Changes-Induced Weight Loss.

Nutrients 2018 Dec 2;10(12). Epub 2018 Dec 2.

Department of Medicine and Aging and Center of Aging Science and Translational Medicine (CESI-Met), University of Chieti, 66100 Chieti, Italy.

Thromboxane (TX)-dependent platelet activation and lipid peroxidation, as reflected in vivo by the urinary excretion of 11-dehydro-TXB₂ and 8-iso-prostaglandin (PG)F, play a key role in atherothrombosis in obesity and type 2 diabetes mellitus (T2DM) since the earlier stages. Thirty-five metformin-treated obese subjects with prediabetes or newly-diagnosed T2DM were randomized to the glucagon-like peptide receptor agonist (GLP-RA) liraglutide (1.8 mg/day) or lifestyle counseling until achieving a comparable weight loss (-7% of initial body weight), to assess whether changes in subcutaneous (SAT) and visceral (VAT) adipose tissue distribution (MRI), insulin sensitivity (Matsuda Index) and beta-cell performance (multiple sampling OGTT beta-index), with either intervention, might affect TX-dependent platelet activation, lipid peroxidation and inflammation. At baseline, Ln-8-iso-PGF (Beta = 0.31, = 0.0088), glycosylated hemoglobin (HbA1c) (Beta = 2.64, = 0.0011) Ln-TNF-α (Beta = 0.58, = 0.0075) and SAT (Beta = 0.14, = 0.044) were significant independent predictors of 11-dehydro-TXB₂. After achievement of the weight loss target, a comparable reduction in U-11-dehydro-TXB₂ (between-group = 0.679) and 8-iso-PGF- ( = 0.985) was observed in both arms in parallel with a comparable improvement in glycemic control, insulin sensitivity, SAT, high-sensitivity C-reactive protein (hs-CRP). In obese patients with initial impairment of glucose metabolism, the extent of platelet activation is related to systemic inflammation, isoprostane formation and degree of glycemic control and abdominal SAT. Successful weight loss, achieved with either lifestyle changes or an incretin-based therapy, is associated with a significant reduction in lipid peroxidation and platelet activation.
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http://dx.doi.org/10.3390/nu10121872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6315606PMC
December 2018

Hypoglycaemia as a function of HbA1c in type 2 diabetes: Insulin glargine 300 U/mL in a patient-level pooled analysis of EDITION 1, 2 and 3.

Diabetes Obes Metab 2019 03 9;21(3):715-719. Epub 2018 Dec 9.

AMCR Institute, Escondido, California.

Basal insulin therapy often involves a compromise between achievement of glycaemic targets and avoidance of hypoglycaemia, dependent on how intensively insulin is titrated. In the Phase 3a EDITION 1, 2 and 3 studies, insulin glargine 300 U/mL (Gla-300) provided glycaemic control equivalent to that of insulin glargine 100 U/mL (Gla-100), with less hypoglycaemia in individuals with type 2 diabetes mellitus (T2DM). The current study evaluated the rates of confirmed (≤3.9 mmol/L [≤70 mg/dL]) or severe hypoglycaemia over six months of treatment with Gla-300 or Gla-100 in the EDITION studies, as a function of HbA1c. Analysis was performed on patient-level data pooled from the three EDITION studies, and annualized hypoglycaemia rate as a function of HbA1c at Month 6 was fitted using a negative binomial regression model. Participants treated with Gla-300 experienced a consistently lower rate of confirmed (≤3.9 mmol/L [≤70 mg/dL]) or severe hypoglycaemia as compared with those treated with Gla-100, regardless of HbA1c at Month 6. Results suggest that treatment with Gla-300 vs Gla-100 could allow individuals with T2DM to achieve equivalent glycaemic control with less hypoglycaemia.
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http://dx.doi.org/10.1111/dom.13578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587758PMC
March 2019

Associations Between Pancreatic Lipids and β-Cell Function in Black African and White European Men With Type 2 Diabetes.

J Clin Endocrinol Metab 2019 04;104(4):1201-1210

Department of Diabetes, School of Life Course Sciences, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.

Context: Intrapancreatic lipid (IPL) has been linked to β-cell dysfunction. Black populations disproportionately develop type 2 diabetes (T2D) and show distinctions in β-cell function compared with white populations.

Objective: We quantified IPL in white European (WE) and black West African (BWA) men with early T2D and investigated the relationships between IPL and β-cell insulin secretory function (ISF).

Design, Setting, And Participants: We performed a cross-sectional assessment of 18 WE and 19 BWA middle-age men with early T2D as part of the South London Diabetes and Ethnicity Phenotyping study.

Main Outcome Measures: The participants underwent Dixon MRI to determine IPL in the pancreatic head, body, and tail and subcutaneous and visceral adipose tissue volumes. Modeled first- and second-phase ISFs were comprehensively determined using C-peptide measurements during a 3-hour meal tolerance test and a 2-hour hyperglycemic clamp test.

Results: The WE men had greater mean IPL levels compared with BWA men (P = 0.029), mainly owing to greater IPL levels in the pancreatic head (P = 0.009). The mean IPL level was inversely associated with orally stimulated first-phase ISF in WE but not BWA men (WE, r = -0.554, P = 0.026; BWA, r = -0.183, P = 0.468). No association was found with orally stimulated second-phase ISF in either WE or BWA men. No associations were found between the mean IPL level and intravenously stimulated ISF.

Conclusions: The IPL levels were lower in BWA than WE men with early T2D, and the lack of inverse association with first-phase ISF in BWA men indicates that IPL might be a less important determinant of the development of T2D in BWA than in WE men.
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http://dx.doi.org/10.1210/jc.2018-01809DOI Listing
April 2019

A renal genetic risk score (GRS) is associated with kidney dysfunction in people with type 2 diabetes.

Diabetes Res Clin Pract 2018 Oct 25;144:137-143. Epub 2018 Aug 25.

Department of Medicine and Surgery, University of Parma, Parma, Italy; Division of Endocrinology and Metabolic Diseases, Azienda Ospedaliera Universitaria di Parma, Parma, Italy.

This study aims to investigate whether renal and cardiovascular phenotypes in Italian patients with type 2 diabetes (T2D) could be influenced by a number of disease risk SNPs recently found in genome-wide association studies (GWAS). In 1591 Italian subjects with T2D: (1) 47 SNPs associated to kidney function and/or chronic kidney disease (CKD) and 49 SNPs associated to cardiovascular disease (CVD) risk were genotyped; (2) urinary albumin/creatinine (A/C) ratio, glomerular filtration rate (eGFR) and lipid profile were assessed; (3) a standard electrocardiogram was performed; (4) two genotype risk scores (GRS) were computed (a renal GRS calculated selecting 39 SNPs associated with intermediate traits of kidney damage and a cardiovascular GRS determined selecting 42 SNPs associated to CVD risk phenotypes). After correction for multiple comparisons, the renal GRS was not associated to A/C ratio (p = 0.33), but it was significantly related to decreased eGFR (p = 0.005). No association between the cardiovascular GRS and electrocardiogram was detected. Thus, in Italian patients with T2D a renal GRS might predict the decline in glomerular function, suggesting that the clock of diabetes associated CKD starts ticking long before hyperglycemia. Our data support the feasibility of gene-based prediction of complications in people with T2D.
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http://dx.doi.org/10.1016/j.diabres.2018.08.013DOI Listing
October 2018

Switching to insulin glargine 300 U/mL: Is duration of prior basal insulin therapy important?

Diabetes Res Clin Pract 2018 Aug 9;142:19-25. Epub 2018 Apr 9.

Division of Endocrinology and Metabolism, Emory University School of Medicine, Atlanta, GA, USA. Electronic address:

Aims: To assess the impact of duration of prior basal insulin therapy on study outcomes in people with type 2 diabetes mellitus receiving insulin glargine 300 U/mL (Gla-300) or insulin glargine 100 U/mL (Gla-100) for 6 months.

Methods: A post hoc patient-level meta-analysis of data from the EDITION 1 and 2 studies. Outcomes included: HbA, percentage of participants with ≥1 confirmed or severe hypoglycaemic event at night (00:00-05:59 h) or any time (24 h), and body weight change. Data were analysed according to duration of prior basal insulin use: >0-≤2 years, >2-≤5 years, >5 years.

Results: This meta-analysis included 1618 participants. HbA change from baseline to month 6 was comparable between Gla-300 and Gla-100 groups, regardless of duration of prior basal insulin therapy. The lower risk with Gla-300 versus Gla-100 of ≥1 confirmed (≤3.9 mmol/L [≤70 mg/dL]) or severe hypoglycaemic event, at night or any time (24 h), was unaffected by duration of prior basal insulin therapy. Similarly, weight change was unaffected by duration of prior basal insulin therapy.

Conclusions: Switching to Gla-300 from other basal insulin therapies provided comparable glycaemic control with lower risk of hypoglycaemia versus Gla-100, regardless of duration of prior basal insulin therapy.

Clinical Trial Registration: NCT01499082, NCT01499095 (ClinicalTrials.gov).
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http://dx.doi.org/10.1016/j.diabres.2018.03.041DOI Listing
August 2018

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

Nutrients 2018 Feb 14;10(2). Epub 2018 Feb 14.

The Laboratory of Phytochemicals in Physiology, Department of Food and Drug, University of Parma, 43125 Parma, Italy.

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.
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http://dx.doi.org/10.3390/nu10020211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5852787PMC
February 2018

Claimed effects, outcome variables and methods of measurement for health claims proposed under European Community Regulation 1924/2006 in the area of blood glucose and insulin concentrations.

Acta Diabetol 2018 Apr 30;55(4):391-404. Epub 2018 Jan 30.

The Laboratory of Phytochemicals in Physiology, Department of Food and Drug, University of Parma, Medical School, Building A, Via Volturno 39, 43125, Parma, Italy.

Most requests for authorization to bear health claims under Articles 13(5) and 14 related to blood glucose and insulin concentration/regulation presented to the European Food Safety Authority (EFSA) receive a negative opinion. Reasons for such decisions are mainly ascribable to poor substantiation of the claimed effects. In this scenario, a project was carried out aiming at critically analysing the outcome variables (OVs) and methods of measurement (MMs) to be used to substantiate health claims, with the final purpose to improve the quality of applications provided by stakeholders to EFSA. This manuscript provides a position statement of the experts involved in the project, reporting the results of an investigation aimed to collect, collate and critically analyse the information relevant to claimed effects (CEs), OVs and MMs related to blood glucose and insulin levels and homoeostasis compliant with Regulation 1924/2006. The critical analysis of OVs and MMs was performed with the aid of the pertinent scientific literature and was aimed at defining their appropriateness (alone or in combination with others) to support a specific CE. The results can be used to properly select OVs and MMs in a randomized controlled trial, for an effective substantiation of the claims, using the reference method(s) whenever available. Moreover, results can help EFSA in updating the guidance for the scientific requirements of health claims.
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http://dx.doi.org/10.1007/s00592-017-1095-6DOI Listing
April 2018

Claimed effects, outcome variables and methods of measurement for health claims on foods related to the gastrointestinal tract proposed under regulation (EC) 1924/2006.

Int J Food Sci Nutr 2018 Nov 29;69(7):771-804. Epub 2018 Jan 29.

a Department of Food and Drugs, The Laboratory of Phytochemicals in Physiology , University of Parma , Parma , Italy.

Most of the requests of authorisation to the use of health claims pursuant to Regulation EC 1924/2006 related to the gastrointestinal (GI) tract have received a negative opinion by the European Food Safety Authority (EFSA), mainly because of an insufficient substantiation of the claimed effect (CE). The present manuscript refers to the collection, collation and critical analysis of outcome variables (OVs) and methods of measurement (MMs) related to the GI tract compliant with Regulation 1924/2006. The critical evaluation of OVs and MMs was based on the literature review, with the final aim of defining their appropriateness in the context of a specific CE. The results obtained are relevant for the choice of the best OVs and MMs to be used in randomised controlled trials aimed to substantiate the claims on the GI tract. Moreover, the results can be used by EFSA for updating the guidance for the scientific requirements of such health claims.
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http://dx.doi.org/10.1080/09637486.2018.1427220DOI Listing
November 2018

Claimed Effects, Outcome Variables and Methods of Measurement for Health Claims Proposed Under European Community Regulation 1924/2006 in the Framework of Maintenance of Skin Function.

Nutrients 2017 Dec 22;10(1). Epub 2017 Dec 22.

The Laboratory of Phytochemicals in Physiology, Department of Food and Drug, University of Parma, 43125 Parma, Italy.

Evidence suggests a protective role for several nutrients and foods in the maintenance of skin function. Nevertheless, all the requests for authorization to use health claims under Article 13(5) in the framework of maintenance of skin function presented to the European Food Safety Authority (EFSA) have received a negative opinion. Reasons for such failures are mainly due to an insufficient substantiation of the claimed effects, including the choice of inappropriate outcome variables (OVs) and methods of measurement (MMs). The present paper reports the results of an investigation aimed at collecting, collating and critically analyzing the information with relation to claimed effects (CEs), OVs and MMs related to skin health compliance with Regulation 1924/2006. CEs, OVs and MMs were collected from both the EFSA Guidance document and from the authorization requests of health claims under Article 13(5). The critical analysis of OVs and MMs was based on a literature review, and was aimed at defining their appropriateness (alone or in combination with others) in the context of a specific CE. The results highlight the importance of an adequate choice of OVs and MMs for an effective substantiation of the claims.
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http://dx.doi.org/10.3390/nu10010007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5793235PMC
December 2017

Bioavailability of Bergamot (Citrus bergamia) Flavanones and Biological Activity of Their Circulating Metabolites in Human Pro-Angiogenic Cells.

Nutrients 2017 Dec 6;9(12). Epub 2017 Dec 6.

Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy.

Myeloid angiogenic cells (MACs) play a key role in endothelial repairing processes and functionality but their activity may be impaired by the lipotoxic effects of some molecules like stearic acid (SA). Among the dietary components potentially able to modulate endothelial function in vivo, (poly)phenolic compounds represent serious candidates. Here, we apply a comprehensive multidisciplinary approach to shed light on the prospects of Bergamot (), a citrus fruit rich in flavanones and other phenolic compounds, in the framework of lipotoxicity-induced MACs impairment. The flavanone profile of bergamot juice was characterized and 16 compounds were identified, with a new 3-hydroxy-3-methylglutaryl (HMG) flavanone, isosakuranetin-7--neohesperidoside-6″--HMG, described for the first time. Then, a pilot bioavailability study was conducted in healthy volunteers to assess the circulating flavanone metabolites in plasma and urine after consumption of bergamot juice. Up to 12 flavanone phase II conjugates (sulfates and glucuronides of hesperetin, naringenin and eriodyctiol) were detected and quantified. Finally, the effect of some of the metabolites identified in vivo, namely hesperetin-7--glucuronide, hesperetin-3'--glucuronide, naringenin-7--glucuronide and naringenin-4'--glucuronide, was tested, at physiological concentrations, on gene expression of inflammatory markers and apoptosis in MACs exposed to SA. Under these conditions, naringenin-4'--glucuronide and hesperetin-7--glucuronide were able to modulate inflammation, while no flavanone glucuronide was effective in curbing stearate-induced lipoapoptosis. These results demonstrate that some flavanone metabolites, derived from the in vivo transformation of bergamot juice phenolics in humans, may mitigate stearate-induced inflammation in MACs.
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http://dx.doi.org/10.3390/nu9121328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748778PMC
December 2017