Self-management in patients with type 2 diabetes: Group-based versus individual education. A systematic review with meta-analysis of randomized trails.

AIM: Patient education is an essential component of the treatment of type 2 diabetes mellitus (T2DM). The present meta-analysis was aimed at verifying the efficacy of group-based versus individual education for self-management in patients with T2DM. DATA SYNTHESIS: A Medline and Embase search up to January 1st, 2021, was performed, including Randomized Controlled Trials (RCT) with duration>6 months, enrolling patients with T2DM and comparing individual-based with group-based educational programs. The primary outcome was endpoint HbA1c; secondary endpoints were lipid profile, body weight, blood pressure, patients' adherence/knowledge, and quality of life. The weighed difference in means (WMD) and Mantel-Haenzel Odds Ratio (MH-OR), with 95% Confidence Interval (CI), were calculated. We retrieved 14 RCT. No significant between-group difference in HbA1c (WMD -0.39[-0.89; 0.09] mmol/mol, p = 0.11) was observed. At metaregression analyses, longer trial duration, higher baseline mean age and duration of diabetes, and lower baseline HbA1c were correlated with greater efficacy of group-based programs in reducing HbA1c. When analyzed separately, trials excluding insulin-treated patients showed a significant reduction of HbA1c in favor of group education. CONCLUSIONS: In patients with T2DM, group education has similar efficacy as individual education on glucose control. Group programs are associated with an improved quality of life and patients' knowledge. PROSPERO AND OSF REGISTRATION: ID243149.

Reduced Thiamine Availability and Hyperglycemia Impair Thiamine Transport in Renal Glomerular Cells through Modulation of Thiamine Transporter 2.

Thiamine helps transketolase in removing toxic metabolites, counteracting high glucose-induced damage in microvascular cells, and progression of diabetic retinopathy/nephropathy in diabetic animals. Diabetic subjects show reduced thiamine levels. Hyperglycemia and reduced thiamine availability concur in impairing thiamine transport inside the blood-retinal barrier, with thiamine transporter-2 (THTR2) primarily involved. Here, we examined the behavior of thiamine transporter-1 (THTR1), THTR2, and their transcription factor Sp1 in response to high glucose and altered thiamine availability in renal cells involved in diabetic nephropathy. Human proximal tubule epithelial cells, podocytes, glomerular endothelial, and mesangial cells were exposed to high glucose and/or thiamine deficiency/oversupplementation. Localization and modulation of THTR1, THTR2, and Sp1; intracellular thiamine; transketolase activity; and permeability to thiamine were examined. Reduced thiamine availability and hyperglycemia impaired thiamine transport and THTR2/Sp1 expression. Intracellular thiamine, transketolase activity, and permeability were strongly dependent on thiamine concentrations and, partly, excess glucose. Glomerular endothelial cells were the most affected by the microenvironmental conditions. Our results confirmed the primary role of THTR2 in altered thiamine transport in cells involved in diabetic microvascular complications. Lack of thiamine concurs with hyperglycemia in impairing thiamine transport. Thiamine supplementation could represent a therapeutic option to prevent or slow the progression of these complications.

Self-management education may improve blood pressure in people with type 2 diabetes. A randomized controlled clinical trial.

BACKGROUND AND AIMS: Diabetes is a suitable model to evaluate intervention programmes aimed at chronic diseases, because of its well-defined and measurable process and outcome indicators. In this study, we aimed at investigating the effects of group based self-management education on clinical and psychological variables in type 2 diabetes. METHODS AND RESULTS: Four-year randomized controlled clinical trial (ISRCTN14558376) comparing Group Care and traditional one-to-one care. Clinical and psychological variables were monitored at baseline, 2 and 4 years. Although differences between groups appear to be non-significant at univariate analysis, body weight, BMI and HbA1c, systolic and diastolic blood pressure improved in the patients followed by Group Care but not among Controls. Prescription of lipid-lowering and anti-hypertensive agents did not change among the patients on Group Care, whereas anti-hypertensives were stepped up among Controls without improving their blood pressure. Multivariable analysis suggests that blood pressure improvement among patients on Group Care was independent of BMI, duration of diabetes and antihypertensive medication, suggesting a direct effect of education, presumably by increasing adherence. The "Powerful Others" dimension of the Locus of Control worsened and fear of complications decreased among Controls. CONCLUSIONS: The results confirm that a multidisciplinary structured group educational approach improves blood pressure, presumably through better adherence to healthy lifestyle and medication, in people with type 2 diabetes. CLINICAL TRIAL REGISTRATION NUMBER: ISRCTN14558376.

Effects of thiamine and fenofibrate on high glucose and hypoxia-induced damage in cell models of the inner blood-retinal barrier.

AIMS: Although diabetic retinopathy has long been considered a microvascular complication, retinal neurodegeneration and inflammation may precede its clinical manifestations. Despite all research efforts, the primary treatment options remain laser photocoagulation and anti-vascular endothelial growth factor (VEGF) intravitreal injections, both aggressive and targeting the late stages of the disease. Medical treatments addressing the early phases of diabetic retinopathy are therefore needed. We aimed at verifying if thiamine and fenofibrate protect the cells of the inner blood-retinal barrier from the metabolic stress induced by diabetic-like conditions. METHODS: Human microvascular endothelial cells (HMECs), retinal pericytes (HRPs) and Müller cells (MIO-M1) were cultured in intermittent high glucose (intHG) and/or hypoxia, with addition of fenofibrate or thiamine. Modulation of adhesion molecules and angiogenic factors was addressed. RESULTS: Integrins ß1/αVß3 and ICAM1 were upregulated in HMECs/HRPs cultured in diabetic-like conditions, as well as metalloproteases MMP2/9 in HRP, with a reduction in their inhibitor TIMP1; MMP2 increased also in HMEC, and TIMP1 decreased in MIO-M1. VEGF and HIF-1α were strongly increased in HMEC in intHG + hypoxia, and VEGF also in HRP. Ang-1/2 augmented in HMEC/MIO-M1, and MCP-1 in HRP/MIO-M1 in intHG + hypoxia. Thiamine was able to normalize all such abnormal modulations, while fenofibrate had effects in few cases only. CONCLUSIONS: We suggest that endothelial cells and pericytes are more affected than Müller cells by diabetic-like conditions. Fenofibrate shows a controversial behavior, potentially positive on Müller cells and pericytes, but possibly detrimental to endothelium, while thiamine confirms once more to be an effective agent in reducing diabetes-induced retinal damage.

Thiamine transporter 2 is involved in high glucose-induced damage and altered thiamine availability in cell models of diabetic retinopathy.

Thiamine prevents high glucose-induced damage in microvasculature, and progression of retinopathy and nephropathy in diabetic animals. Impaired thiamine availability causes renal damage in diabetic patients. Two single-nucleotide polymorphisms in SLC19A3 locus encoding for thiamine transporter 2 are associated with absent/minimal diabetic retinopathy and nephropathy despite long-term type 1 diabetes. We investigated the involvement of thiamine transporter 1 and thiamine transporter 2, and their transcription factor specificity protein 1, in high glucose-induced damage and altered thiamine availability in cells of the inner blood-retinal barrier. Human endothelial cells, pericytes and Müller cells were exposed to hyperglycaemic-like conditions and/or thiamine deficiency/over-supplementation in single/co-cultures. Expression and localization of thiamine transporter 1, thiamine transporter 2 and transcription factor specificity protein 1 were evaluated together with intracellular thiamine concentration, transketolase activity and permeability to thiamine. The effects of thiamine depletion on cell function (viability, apoptosis and migration) were also addressed. Thiamine transporter 2 and transcription factor specificity protein 1 expression were modulated by hyperglycaemic-like conditions. Transketolase activity, intracellular thiamine and permeability to thiamine were decreased in cells cultured in thiamine deficiency, and in pericytes in hyperglycaemic-like conditions. Thiamine depletion reduced cell viability and proliferation, while thiamine over-supplementation compensated for thiamine transporter 2 reduction by restoring thiamine uptake and transketolase activity. High glucose and reduced thiamine determine impairment in thiamine transport inside retinal cells and through the inner blood-retinal barrier. Thiamine transporter 2 modulation in our cell models suggests its major role in thiamine transport in retinal cells and its involvement in high glucose-induced damage and impaired thiamine availability.

Vision-related quality of life and locus of control in type 1 diabetes: a multicenter observational study.

AIMS: Diabetic retinopathy remains asymptomatic until its late stages but remains a leading cause of vision impairment and blindness. We studied quality of life and the ability to deal with the discomfort deriving from the presence of a chronic disease in patients with type 1 diabetes and different stages of retinopathy. METHODS: Multicenter collaborative observational study involving nine centers screening for retinopathy in different areas of Italy. The National Eye Institute 25-item visual functioning questionnaire and the locus of control tool were administered to 449 people with type 1 diabetes between February 2016 and March 2018. Socio-demographic and clinical data were collected. RESULTS: On multivariable analysis, severe retinopathy is associated with worse scores for general vision, ocular pain, near vision activities, distance vision activities, driving, color vision, peripheral vision and lower values of internal control, independently of visual acuity. Women had a perception of worse general health, distance vision activities and driving, and lower internal control and trust in others. Worse scores for visual-specific social functioning, visual-specific mental health, visual-specific role difficulties, visual-specific dependency and peripheral vision were associated with higher HbA1c levels. Fatalism increased with rising HbA1c levels. CONCLUSIONS: These results confirm that a gap exists between patients' knowledge and expectations on retinopathy and providers' expertise and assumptions. To bridge this gap, patient-centered education and engaging approaches may be more effective than simple information given during consultations.

Dysfunctional eating in type 2 diabetes mellitus: A multicenter Italian study of socio-demographic and clinical associations.

BACKGROUND AND AIMS: Dysfunctional eating might impact on the management and metabolic control of type 2 diabetes (T2DM), modifying adherence to healthy diet and food choices. METHODS AND RESULTS: In a multicenter study, we assessed the prevalence of dysfunctional eating in 895 adult outpatients with T2DM (51% males, median age 67, median BMI 30.3 kg/m2). Socio-demographic and clinical characteristics were recorded; dysfunctional eating was tested by validated questionnaires (Eating Attitude Test-EAT-26, Binge Eating Scale-BES; Night Eating Questionnaire-NEQ); food intake and adherence to Mediterranean diet were also measured (in-house developed questionnaire and Mediterranean Diet Score-MDS). Obesity was present in 52% of cases (10% obesity class III), with higher rates in women; 22% had HbA1c ≥ 8%. The EAT-26 was positive in 19.6% of women vs. 10.2% of men; BES scores outside the normal range were recorded in 9.4% of women and 4.4% of men, with 3.0% and 1.5% suggestive of binge eating disorder, respectively. Night eating (NEQ) was only present in 3.2% of women and 0.4% of men. Critical EAT and BES values were associated with higher BMI, and all NEQ + ve cases, but one, were clustered among BES + ve individuals. Calorie intake increased with BES, NEQ, and BMI, and decreased with age and with higher adherence to Mediterranean diet. In multivariable logistic regression analysis, female sex, and younger age were associated with increase risk of dysfunctional eating. CONCLUSION: Dysfunctional eating is present across the whole spectrum of T2DM and significantly impacts on adherence to dietary restriction and food choices.

Functional analysis of miR-21-3p, miR-30b-5p and miR-150-5p shuttled by extracellular vesicles from diabetic subjects reveals their association with diabetic retinopathy.

Microvascular dysfunctions due to altered interactions between endothelial cells (ECs) and pericytes are key-events in the pathogenesis of diabetic retinopathy. Extracellular vesicles (EVs) derived from mesenchymal stem cells cultured in diabetic-like conditions enter pericytes, cause their detachment and migration, and stimulate angiogenesis. We recently showed that EVs from diabetic patients with retinopathy have different miRNA profiling patterns from healthy controls, and determine features of retinopathy in in vitro models of retinal microvasculature. In particular, a role for intra-vesicle miR-150-5p, miR-21-3p and miR-30b-5p was hypothesized. In this work, we further characterized EVs from subjects with diabetic retinopathy and investigated miR-150-5p, miR-21-3p and miR-30b-5p functions inside microvascular cells. Human retinal pericytes and ECs were transfected with mimics or inhibitors, as appropriate, of miR-21-3p, miR-30b-5p and miR-150-5p, to evaluate their ability in promoting cell migration and tube formation. mRNA and protein profiling of EVs extracted from diabetic subjects with (DR group) or without retinopathy (noDR group), and healthy controls (CTR group) were also performed. Modulation of miR-150-5p, miR-21-3p and miR-30b-5p inside microvascular cells confirmed their involvement in abnormal angiogenesis. mRNA analysis revealed differing expression of 7 genes involved in angiogenesis, while subsequent protein analysis confirmed increased expression of HIF-1α in DR group. Since all these molecules are involved in the hypoxia-induced retinal damage characteristic of the disease, our data reinforce the hypothesis of a potential use of miR-150-5p, miR-21-3p and miR-30b-5p extracted from circulating EVs as prognostic biomarkers for diabetic retinopathy.

The co-activator-associated arginine methyltransferase 1 (CARM1) gene is overexpressed in type 2 diabetes.

PURPOSE: We examined the expression of a panel of epigenetic enzymes catalyzing histone tails post-transcriptional modifications, together with effectors of metabolic and inflammatory alterations, in type 2 diabetes. METHODS: Cross-sectional, case-control study of 21 people with type 2 diabetes and 21 matched controls. Total RNA was extracted from white cells and reverse transcribed. PCR primer assays for 84 key genes encoding enzymes known to modify genomic DNA and histones were performed. Western blot was performed on lysates using primary antibodies for abnormally expressed enzymes. Hormones and cytokines were measured by multiplex kits. A Bayesian network was built to investigate the relationships between epigenetic, cytokine, and endocrine variables. RESULTS: Co-activator-associated aRginine Methyltransferase 1 (CARM1) expression showed a five-fold higher median value, matched by higher protein levels, among patients who also had increased GIP, IL-4, IL-7, IL-13, IL-17, FGF basic, G-CSF, IFN-γ, and TNFα and decreased IP-10. In a Bayesian network approach, CARM1 expression showed a conditional dependence on diabetes, but was independent of all other variables nor appeared to influence any. CONCLUSIONS: Increased CARM1 expression in type 2 diabetes suggests that epigenetic mechanisms are altered in human diabetes. The impact of lifestyle and pharmacological treatment on regulation of this enzyme should be further investigated.

Type 2 diabetes affects bone cells precursors and bone turnover.

BACKGROUND: Here we study the effect of type 2 diabetes (T2DM) on bone cell precursors, turnover and cytokines involved in the control of bone cell formation and activity. METHODS: We enrolled in the study 21 T2DM women and 21 non diabetic controls matched for age and body mass index (BMI). In each subject we measured bone cell precursors, Receptor Activator of Nuclear Factor κB (RANKL), Osteoprotegerin (OPG), Sclerostin (SCL) and Dickoppf-1 (DKK-1) as cytokines involved in the control of osteoblast and osteoclast formation and activity, bone density (BMD) and quality trough trabecular bone score (TBS) and bone turnover. T2DM patients and controls were compared for the analyzed variables by one way ANOVA for Gaussian ones and by Mann-Whitney or Kruskal-Wallis test for non-Gaussian variables. RESULTS: RANKL was decreased and DKK-1 increased in T2DM. Accordingly, patients with T2DM have lower bone turnover compared to controls. BMD and TBS were not significantly different from healthy controls. Bone precursor cells were more immature in T2DM. However the number of osteoclast precursors was increased and that of osteoblasts decreased. CONCLUSIONS: Patients with T2DM have more immature bone cells precursors, with increased number of osteoclasts and decreased osteoblasts, confirming low bone turnover and reduced cytokines such as RANKL and DKK-1. BMD and TBS are not significantly altered in T2DM although, in contrast with other studies, this may be due to the match of patients and controls for BMI rather than age.

Molecular and functional characterization of circulating extracellular vesicles from diabetic patients with and without retinopathy and healthy subjects.

Diabetic retinopathy is a sight-threatening complication of diabetes, characterized by loss of retinal pericytes and abnormal angiogenesis. We previously demonstrated that extracellular vesicles (EVs) derived from mesenchymal stem cells cultured in diabetic-like conditions are able to enter the pericytes, causing their detachment and migration, and stimulating angiogenesis in vitro. The purpose of this work was the molecular and functional characterization of EVs derived from diabetic subjects with or without diabetic retinopathy, compared with healthy controls. Characterization of EVs extracted from serum/plasma of diabetic patients with or without retinopathy, and healthy controls, was performed by FACS and microarray analysis of microRNA (miRNA) content. Relevant miRNA expression was validated through qRT-PCR. EV influence on pericyte detachment, angiogenesis and permeability of the blood-retinal barrier was also investigated. Diabetic subjects had a 2.5 fold higher EV concentration than controls, while expression of surface molecules was unchanged. Microarray analysis revealed 11 differentially expressed miRNAs. Three of them (miR-150-5p, miR-21-3p and miR-30b-5p) were confirmed by qRT-PCR. Plasma EVs from subjects with diabetic retinopathy induced pericyte detachment and pericyte/endothelial cell migration, increased the permeability of pericyte/endothelial cell bilayers and the formation of vessel-like structures, when compared with EVs from controls. In conclusion, circulating EVs show differences between diabetic patients and healthy subjects. EVs extracted from plasma of diabetic retinopathy patients are able to induce features of retinopathy in in vitro models of retinal microvasculature. Our data suggest a role for miR-150-5p, miR-21-3p and miR-30b-5p as potential biomarkers of the onset of diabetic retinopathy.

Detection of perimacular red dots and blots when screening for diabetic retinopathy: Refer or not refer?

PURPOSE: Detection of microaneurysms and/or microhaemorrhages near the fovea when screening for diabetic retinopathy poses a problem because referral to retinal specialists may alarm patients and unnecessarily burden ophthalmologists. METHODS: Six-month prospective study of patients found to have minimal red lesions within one disc diameter of the fovea when screened for diabetic retinopathy. Two 45° digital photographs, one centred on the macula and the other nasal including the optic disc, were taken for each eye. All patients received a 6-month re-screening appointment. RESULTS: Out of 70 patients, 41 returned for re-screening. Diabetic retinopathy had worsened in 3 who required referral but no treatment, was unchanged in 19 and was undetectable in the other 19. Haemoglobin A1c decreased from 7.76% ± 1.50% (61.3 ± 16.2 mmol/mol) to 6.93% ± 1.7% (52.3 ± 18.9 mmol/mol) in the patients in whom diabetic retinopathy worsened but did not change in the other groups. Baseline haemoglobin A1c ( p = 0.048) and systolic blood pressure ( p = 0.007) were lower in the patients in whom diabetic retinopathy improved, but a multivariate model including haemoglobin A1c, blood pressure and known disease duration could not identify any independent risk factor. CONCLUSION: Minimal red lesions near the fovea, though commanding early re-screening, do not require immediate referral to retinal specialists.

Self-knowledge of HbA1c in people with Type 2 Diabetes Mellitus and its association with glycaemic control.

OBJECTIVE: The aim of this study was to evaluate the prevalence of accurate self-knowledge of a patient's own HbA1c level (HbA1cSK), as a component of structural education (University Hospital's of Leicester (UHL), 2013) and its association with glycaemic control. METHODS: Data from the GUIDANCE study, a cross-sectional study involving 7597 participants from eight European countries was used. HbA1cSK was evaluated and compared with laboratory measured HbA1c levels (HbA1cLAB), which represented the measure of glycaemic control. Accuracy of the self-reported HbA1c was evaluated by using agreement statistical methods. RESULTS: The prevalence of HbA1cSK was 49.4%. Within this group, 78.3% of the participants had accurately reported HbA1cSK. There was good level of agreement between HbA1cSK and HbA1cLAB (intra-class correlation statistic=0.84, p<0.0001). Participants with accurately reported HbA1cSK were found to have a statistically significantly lower HbA1cLAB compared to participants with inaccurately reported HbA1cSK (7.0% versus 7.3%, p<0.001). CONCLUSION: Nearly half of the patients had self-knowledge of their own HbA1c level. Moreover, the participants with accurately reported HbA1cSK were found to have associated better glycaemic control.