Randomized trials demonstrated a lower risk of cardiovascular (CV) events with sodium-glucose cotransporter-2 inhibitors (SGLT-2i) in patients with type 2 diabetes (T2D) at high CV risk. Prior ...real-world data suggested similar SGLT-2i effects in T2D patients with a broader risk profile, but these studies focused on heart failure and death and were limited to the United States and Europe.
The purpose of this study was to examine a broad range of CV outcomes in patients initiated on SGLT-2i versus other glucose-lowering drugs (oGLDs) across 6 countries in the Asia Pacific, the Middle East, and North American regions.
New users of SGLT-2i and oGLDs were identified via claims, medical records, and national registries in South Korea, Japan, Singapore, Israel, Australia, and Canada. Propensity scores for SGLT-2i initiation were developed in each country, with 1:1 matching. Hazard ratios (HRs) for death, hospitalization for heart failure (HHF), death or HHF, MI, and stroke were assessed by country and pooled using weighted meta-analysis.
After propensity-matching, there were 235,064 episodes of treatment initiation in each group; ∼27% had established CV disease. Patient characteristics were well-balanced between groups. Dapagliflozin, empagliflozin, ipragliflozin, canagliflozin, tofogliflozin, and luseogliflozin accounted for 75%, 9%, 8%, 4%, 3%, and 1% of exposure time in the SGLT-2i group, respectively. Use of SGLT-2i versus oGLDs was associated with a lower risk of death (HR: 0.51; 95% confidence interval CI: 0.37 to 0.70; p < 0.001), HHF (HR: 0.64; 95% CI: 0.50 to 0.82; p = 0.001), death or HHF (HR: 0.60; 95% CI: 0.47 to 0.76; p < 0.001), MI (HR: 0.81; 95% CI: 0.74 to 0.88; p < 0.001), and stroke (HR: 0.68; 95% CI: 0.55 to 0.84; p < 0.001). Results were directionally consistent across both countries and patient subgroups, including those with and without CV disease.
In this large, international study of patients with T2D from the Asia Pacific, the Middle East, and North America, initiation of SGLT-2i was associated with a lower risk of CV events across a broad range of outcomes and patient characteristics. (Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors CVD-REAL; NCT02993614).
Aims
To estimate the incidence of Type 2 diabetes in children aged <17 years, compare this with similar data 10 years ago, and characterize clinical features at diagnosis in the UK and Republic of ...Ireland.
Methods
Using the British Paediatric Surveillance Unit reporting framework, cases of Type 2 diabetes diagnosed in children aged <17 years between 1 April 2015 and 30 April 2016 were reported each month.
Results
A total of 106 cases were reported, giving a UK incidence of 0.72/100 000 (95% CI 0.58–0.88). Children from ethnic minorities had significantly higher incidence compared with white children (0.44/100 000) with rates of 2.92/100 000 and 1.67/100 000, in Asian and BACBB (black/African/Caribbean/black British) children respectively. Sixty‐seven percent were girls and 81% had a family history of Type 2 diabetes. The mean BMI sd score at diagnosis was 2.89 (2.88, girls; 2.92, boys); 81% were obese. Children of Asian ethnicity had a significantly lower BMI sd score compared with white children (P<0.001). There was a trend in increased incidence from 2005 to 2015, with a rate ratio of 1.35 (95% CI 0.99–1.84), although this was not statistically significant (P=0.062). There was statistical evidence of increased incidence among girls (P=0.03) and children of South‐Asian ethnicity (P=0.01) when comparing the 2005 and 2015 surveys.
Conclusions
Type 2 diabetes remains far less common than Type 1 diabetes in childhood in the UK, but the number of cases continues to rise, with significantly increased incidence among girls and South‐Asian children over a decade. Female gender, family history, non‐white ethnicity and obesity were found to be strongly associated with the condition.
What's new?
The 2015/2016 UK incidence of Type 2 diabetes in children aged <17 years was 0.72 per 100 000 per year
The incidence of Type 2 diabetes amongst girls and South‐Asian children has risen significantly over the last decade.
Female gender, family history, non‐white ethnicity and obesity were strongly associated with Type 2 diabetes in childhood.
Comorbidities are commonly identified at diagnosis, including 37% with non‐alcoholic fatty liver disease and 21% with hypertension
The most common presenting complaint at diagnosis after osmotic symptoms (polyuria, polydipsia and weight loss) was recurrent, mainly genital, infections, although over a third of cases were asymptomatic and detected on obesity screening investigations
Optimal glycaemic control before and during pregnancy improves both maternal and fetal outcomes. This article summarizes the recently published guidelines on the management of glycaemic control in ...pregnant women with diabetes on obstetric wards and delivery units produced by the Joint British Diabetes Societies for Inpatient Care and available in full at www.diabetes.org.uk/joint-british-diabetes-society and https://abcd.care/joint-british-diabetes-societies-jbds-inpatient-care-group. Hyperglycaemia following steroid administration can be managed by variable rate intravenous insulin infusion (VRIII) or continuous subcutaneous insulin infusion (CSII) in women who are willing and able to safely self‐manage insulin dose adjustment. All women with diabetes should have capillary blood glucose (CBG) measured hourly once they are in established labour. Those who are found to be higher than 7 mmol/l on two consecutive occasions should be started on VRIII. If general anaesthesia is used, CBG should be monitored every 30 min in the theatre. Both the VRIII and CSII rate should be reduced by at least 50% once the placenta is delivered. The insulin dose needed after delivery in insulin‐treated Type 2 and Type 1 diabetes is usually 25% less than the doses needed at the end of first trimester. Additional snacks may be needed after delivery especially if breastfeeding. Stop all anti‐diabetes medications after delivery in gestational diabetes. Continue to monitor CBG before and 1 h after meals for up to 24 h after delivery to pick up any pre‐existing diabetes or new‐onset diabetes in pregnancy. Women with Type 2 diabetes on oral treatment can continue to take metformin after birth.
What's new?
The benefits of optimal maternal glycaemia are clear but how to achieve it during the gestational challenges of antenatal steroid administration, labour and birth remains unclear.
The current guideline suggests a simple standardized approach to achieve the recommended National Institute for Health and Care Excellence targets of glycaemic control in a safe and effective manner.
Improving maternal glycaemia before and during delivery may help to reduce the burden of neonatal hypoglycaemia and clinic‐to‐clinic variation in neonatal intensive care unit admissions.
Type 2 diabetes is now a pandemic and shows no signs of abatement. In this Seminar we review the pathophysiology of this disorder, with particular attention to epidemiology, genetics, epigenetics, ...and molecular cell biology. Evidence is emerging that a substantial part of diabetes susceptibility is acquired early in life, probably owing to fetal or neonatal programming via epigenetic phenomena. Maternal and early childhood health might, therefore, be crucial to the development of effective prevention strategies. Diabetes develops because of inadequate islet β-cell and adipose-tissue responses to chronic fuel excess, which results in so-called nutrient spillover, insulin resistance, and metabolic stress. The latter damages multiple organs. Insulin resistance, while forcing β cells to work harder, might also have an important defensive role against nutrient-related toxic effects in tissues such as the heart. Reversal of overnutrition, healing of the β cells, and lessening of adipose tissue defects should be treatment priorities.
Objective. This study investigated if resveratrol ameliorates diabetic cardiomyopathy by targeting associated oxidative stress mechanisms. Method. Type 1 diabetes mellitus (DM) in FVB mice was ...induced by several intraperitoneal injections of a low dose of streptozotocin. Hyperglycemic and age-matched control mice were given resveratrol (10 mg/kg per day) for 1 month and subsequently monitored for an additional 6 months. Mice were assigned to four groups: control, resveratrol, DM, and DM/resveratrol. Cardiac function and blood pressure were assessed at 1, 3, and 6 months after DM induction. Oxidative damage and cardiac fibrosis were analyzed by histopathology, real-time PCR, and Western blot. Result. Mice in the DM group exhibited increased blood glucose levels, cardiac dysfunction, and high blood pressure at 1, 3, and 6 months after DM induction. Resveratrol did not significantly affect blood glucose levels and blood pressure; however, resveratrol attenuated cardiac dysfunction and hypertrophy in DM mice. Resveratrol also reduced DM-induced fibrosis. In addition, DM mice hearts exhibited increased oxidative damage, as evidenced by elevated accumulation of 3-nitrotyrosine and 4-hydroxynonenal, which were both attenuated by resveratrol. Mechanistically, resveratrol increased NFE2-related factor 2 (Nrf2) expression and transcriptional activity, as well as Nrf2’s downstream antioxidative targets. Conclusion. We demonstrated that resveratrol prevents DM-induced cardiomyopathy, in part, by increasing Nrf2 expression and transcriptional activity.
To explore mechanisms by which SGLT2 inhibitors protect diabetic hearts from heart failure, we examined the effect of empagliflozin (Empa) on the ultrastructure of cardiomyocytes in the noninfarcted ...region of the diabetic heart after myocardial infarction (MI). OLETF, a rat model of type 2 diabetes, and its nondiabetic control, LETO, received a sham operation or left coronary artery ligation 12 h before tissue sampling. Tissues were sampled from the posterior ventricle (i.e., the remote noninfarcted region in rats with MI). The number of mitochondria was larger and small mitochondria were more prevalent in OLETF than in LETO. Fis1 expression level was higher in OLETF than in LETO, while phospho‐Ser637‐Drp1, total Drp1, Mfn1/2, and OPA1 levels were comparable. MI further reduced the size of mitochondria with increased Drp1‐Ser616 phosphorylation in OLETF. The number of autophagic vacuoles was unchanged after MI in LETO but was decreased in OLETF. Lipid droplets in cardiomyocytes and tissue triglycerides were increased in OLETF. Empa administration (10 mg/kg per day) reduced blood glucose and triglycerides and paradoxically increased lipid droplets in cardiomyocytes in OLETF. Empa suppressed Fis1 upregulation, increased Bnip3 expression, and prevented reduction in both mitochondrial size and autophagic vacuole number after MI in OLETF. Together with the results of our parallel study showing upregulation of SOD2 and catalase by Empa, the results indicate that Empa normalizes the size and number of mitochondria in diabetic hearts and that diabetes‐induced excessive reduction in mitochondrial size after MI was prevented by Empa via suppression of ROS and restoration of autophagy.
Empagliflozin, an SGLT2 inhibitor, normalized the size and number of mitochondria in diabetic hearts. In addition, this agent prevented diabetes‐induced excess reduction in mitochondrial size in the noninfarcted myocardium after myocardial infarction.
Type 1 diabetes induction in humanized mice Tan, Shulian; Li, Yang; Xia, Jinxing ...
Proceedings of the National Academy of Sciences - PNAS,
10/2017, Letnik:
114, Številka:
41
Journal Article
Recenzirano
Odprti dostop
There is an urgent and unmet need for humanized in vivo models of type 1 diabetes to study immunopathogenesis and immunotherapy, and in particular antigen-specific therapy. Transfer of patient blood ...lymphocytes to immunodeficient mice is associated with xenogeneic graft-versus-host reactivity that complicates assessment of autoimmunity. Improved models could identify which human T cells initiate and participate in beta-cell destruction and help define critical target islet autoantigens. We used humanized mice (hu-mice) containing robust human immune repertoires lacking xenogeneic graft-versus-host reactivity to address this question. Hu-mice constructed by transplantation of HLA-DQ8⁺ human fetal thymus and CD34⁺ cells into HLA-DQ8–transgenic immunodeficient mice developed hyperglycemia and diabetes after transfer of autologous HLA-DQ8/insulin-B:9–23 (InsB:9–23)-specific T-cell receptor (TCR)-expressing human CD4⁺ T cells and immunization with InsB:9–23. Survival of the infused human T cells depended on the preexisting autologous human immune system, and pancreatic infiltration by human CD3⁺ T cells and insulitis were observed in the diabetic hu-mice, provided their islets were stressed by streptozotocin. This study fits Koch’s postulate for pathogenicity, demonstrating a pathogenic role of islet autoreactive CD4⁺ T-cell responses in type 1 diabetes induction in humans, underscores the role of the target beta-cells in their immunological fate, and demonstrates the capacity to initiate disease with T cells, recognizing the InsB:9–23 epitope in the presence of islet inflammation. This preclinical model has the potential to be used in studies of the pathogenesis of type 1 diabetes and for testing of clinically relevant therapeutic interventions.
Diabetes is a common disease marked by high blood sugars. An earlier clinical trial in type 1 diabetic subjects (T1Ds) found that repeat BCG vaccinations succeeded in lowering HbA1c values over a ...multi-year course. Here we seek to determine whether BCG therapy for bladder cancer may improve blood sugar levels in patients with comorbid T1D and type 2 diabetes (T2D). We also investigate whether BCG exposure may reduce onset of T1D and T2D by examining country-by-country impact of BCG childhood vaccination policies in relation to disease incidence.
We first analyzed three large US patient datasets (Optum Labs data N = 45 million, Massachusetts General Brigham N = 6.5 million, and Quest Diagnostics N = 263 million adults), by sorting out subjects with documented T1D (N = 19) or T2D (N = 106) undergoing BCG therapy for bladder cancer, and then by retrospectively assessing BCG's subsequent year-by-year impact on blood sugar trends. Additionally, we performed an ecological analysis of global data to assess the country-by-country associations between mandatory neonatal BCG vaccination programs and T1D and T2D incidence. Multi-dose BCG therapy in adults with comorbid diabetes and bladder cancer was associated with multi-year and stable lowering of HbA1c in T1Ds, but not in T2Ds. The lack of a similar benefit in T2D may be due to concurrent administration of the diabetes drug metformin, which inhibits BCG's beneficial effect on glycolysis pathways. Countries with mandatory neonatal BCG vaccination policies had a lower incidence of T1D in two international databases and a lower incidence of T2D in one of the databases.
The epidemiological evidence analyzed here suggests that BCG may play a role in the prevention of T1D. It does not support prevention of T2D, most likely because of interference by metformin. Our ecological analysis of global data suggests a role for neonatal BCG in the prevention of T1D and, to a lesser extent, T2D. Randomized clinical trials are needed to confirm these findings.
Viral infections may increase the risk of developing type 1 diabetes (T1D), and recent reports suggest that Coronavirus Disease 2019 (COVID‐19) might have increased the incidence of pediatric T1D ...and/or diabetic ketoacidosis (DKA). Therefore, this meta‐analysis aims to estimate the risk of global pediatric new‐onset T1D, DKA, and severe DKA before and after the COVID‐19 pandemic. A systematic search of MEDLINE/PubMed, CINAHL, Scopus, and EMBASE was conducted for articles published up to March 2022. A random‐effects meta‐analysis was performed to compare the relative risk of T1D and DKA among pediatric patients with T1D between the COVID‐19 pre‐pandemic and pandemic periods. We also compared glucose and HbA1c values in children who were newly diagnosed with T1D before and after the COVID‐19 pandemic. The global incidence rate of T1D in the 2019 period was 19.73 per 100 000 children and 32.39 per 100 000 in the 2020 period. Compared with pre‐COVID‐19 pandemic, the number of worldwide pediatric new‐onset T1D, DKA, and severe DKA during the first year of the COVID‐19 pandemic increased by 9.5%, 25%, and 19.5%, respectively. Compared with pre‐COVID‐19 pandemic levels, the median glucose, and HbA1c values in newly diagnosed T1D children after the COVID‐19 pandemic increased by 6.43% and 6.42%, respectively. The COVID‐19 pandemic has significantly increased the risk of global pediatric new‐onset T1D, DKA, and severe DKA. Moreover, higher glucose and HbA1c values in newly diagnosed T1D children after the COVID‐19 pandemic mandates targeted measures to raise public and physician awareness.
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