Real-World Evidence of Off-Label Use of Commercially Automated Insulin Delivery Systems Compared to Multiple Daily Insulin Injections in Pregnancies Complicated by Type 1 Diabetes.

Aims: To compare glycemic control and maternal-fetal outcomes of women with type 1 diabetes (T1D) using hybrid closed loop (HCL) versus multiple daily insulin injections (MDI) plus continuous glucose monitoring. Methods: Multicenter prospective cohort study of pregnant women with T1D in Spain. We evaluated HbA1c and time spent within (TIR), below (TBR), and above (TAR) the pregnancy-specific glucose range of 3.5-7.8 mmol/L. Adjusted models were performed for adverse pregnancy outcomes, including baseline maternal characteristics and center. Results: One hundred twelve women were included (HCL n = 59). Women in the HCL group had a longer duration of diabetes and higher rates of prepregnancy care. There was no between-group difference in HbA1c in any trimester. However, in the second trimester, MDI users had a greater decrease in HbA1c (-6.12 ± 9.06 vs. -2.16 ± 7.42 mmol/mol, P = 0.031). No difference in TIR (3.5-7.8 mmol/L) and TAR was observed between HCL and MDI users, but with a higher total insulin dose in the second trimester [+0.13 IU/kg·day)]. HCL therapy was associated with increased maternal weight gain during pregnancy (ßadjusted = 3.20 kg, 95% confidence interval [CI] 0.90-5.50). Regarding neonatal outcomes, newborns of HCL users were more likely to have higher birthweight (ßadjusted = 279.0 g, 95% CI 39.5-518.5) and macrosomia (ORadjusted = 3.18, 95% CI 1.05-9.67) compared to MDI users. These associations disappeared when maternal weight gain or third trimester HbA1c was included in the models. Conclusions: In a real-world setting, HCL users gained more weight during pregnancy and had larger newborns than MDI users, while achieving similar glycemic control in terms of HbA1c and TIR.

Methodological challenges in systematic reviews of mHealth interventions: Survey and consensus-based recommendations.

OBJECTIVE: Mobile Health (mHealth) refers to using mobile devices to support health. This study aimed to identify specific methodological challenges in systematic reviews (SRs) of mHealth interventions and to develop guidance for addressing selected challenges. STUDY DESIGN AND SETTING: Two-phase participatory research project. First, we sent an online survey to corresponding authors of SRs of mHealth interventions. On a five-category scale, survey respondents rated how challenging they found 24 methodological aspects in SRs of mHealth interventions compared to non-mHealth intervention SRs. Second, a subset of survey respondents participated in an online workshop to discuss recommendations to address the most challenging methodological aspects identified in the survey. Finally, consensus-based recommendations were developed based on the workshop discussion and subsequent interaction via email with the workshop participants and two external mHealth SR authors. RESULTS: We contacted 953 corresponding authors of mHealth intervention SRs, of whom 50 (5 %) completed the survey. All the respondents identified at least one methodological aspect as more or much more challenging in mHealth intervention SRs than in non-mHealth SRs. A median of 11 (IQR 7.25-15) out of 24 aspects (46 %) were rated as more or much more challenging. Those most frequently reported were: defining intervention intensity and components (85 %), extracting mHealth intervention details (71 %), dealing with dynamic research with evolving interventions (70 %), assessing intervention integrity (69 %), defining the intervention (66 %) and maintaining an updated review (65 %). Eleven survey respondents participated in the workshop (five had authored more than three mHealth SRs). Eighteen consensus-based recommendations were developed to address issues related to mHealth intervention integrity and to keep mHealth SRs up to date. CONCLUSION: mHealth SRs present specific methodological challenges compared to non-mHealth interventions, particularly related to intervention integrity and keeping SRs current. Our recommendations for addressing these challenges can improve mHealth SRs.

Impact of PCSK9 inhibitors in glycaemic control and new-onset diabetes.

BACKGROUND: The diabetogenic effect of statins has been well established by clinical trials, Mendelian randomisation studies and meta-analyses. According to large clinical trials, PCSK9 inhibitors (PCSK9i) have no deleterious impact on glucose metabolism. However, few real-life studies have yet evaluated the long-term effects of these drugs on glucose homeostasis and their impact on new-onset diabetes (NODM). METHODS: We studied 218 patients treated with either alirocumab or evolocumab (70% with familial hypercholesterolemia) for at least three years (PCSK9iG). We studied the NODM rate in the nondiabetic group at baseline (168) and overall glucose metabolism control in the whole group. Incidental DM was compared with two groups. The first was a propensity score matching (PSM)-selected group (n = 168) from the database of patients attending the Reus lipid unit (Metbank, n = 745) who were not on PCSK9i (PSMG). The second was a subgroup with a similar age range (n = 563) of the Di@bet.es study (Spanish prospective study on diabetes development n = 5072) (D@G). The incidence was reported as the percentage of NODM cases per year. RESULTS: The fasting glucose (FG) level of the subjects with normoglycaemia at baseline increased from 91 (86-95.5) to 93 (87-101) mg/dL (p = 0.014). There were 14 NODM cases in the PCSK9i group (2.6%/y), all among people with prediabetes at baseline. The incidence of NODM in PSMG and D@G was 1.8%/y (p = 0.69 compared with the PCSK9iG). The incidence among the subjects with prediabetes was 5.1%/y in the PCSK9iG, 4.8%/y in the PSMG and 3.9%/y in the D@G (p = 0.922 and p = 0.682, respectively). In the multivariate analysis, only the FG level was associated with the development of NODM in the PCSK9iG (OR 1.1; 95% CI: 1.0-1.3; p = 0.027). Neither FG nor A1c levels changed significantly in patients with DM at baseline. CONCLUSION: A nonsignificant increase in NODM occurred in the PCSK9iG, particularly in patients with prediabetes, compared with the PSMG and D@G groups. Baseline FG levels were the main variable associated with the development of DM. In the subjects who had DM at baseline, glucose control did not change. The impact of PCSK9i on glucose metabolism should not be of concern when prescribing these therapies.

Maternal age, obesity and hyperglycaemia are associated with a delay in preimplantation embryo development in mouse.

In brief: Fertility has decreased due to advanced maternal age and the rising prevalence of the metabolic syndrome. Using quantitative image analysis methods, we show that these factors are associated with delayed preimplantation embryo development in a mouse model. Abstract: Delayed maternal age, obesity and diabetes are associated with reduced fertility. We investigated how age and obesity/metabolic syndrome impact fertility and hypothesized that its decrease is due to defects in preimplantation embryo development. Three groups of female C57Bl6 mice (12 weeks, 9 months and 1 year old) were fed either a high-fat diet for 8 weeks, to induce obesity and the metabolic syndrome, or a control chow diet. Body weight and composition, glucose tolerance and insulin resistance were assessed. Fecundity was evaluated by mating and pregnancy rates, as well as by the number of embryos. Embryo quality was assessed morphologically, and cell fate composition was analysed in preimplantation embryos by state-of-the-art single-cell quantitative confocal image analysis. The high-fat diet was associated with increased adiposity, glucose intolerance and insulin resistance, especially in the older mice. Fecundity was affected by age more than by the diet. Both age and high-fat diet were associated with reduced cell fate allocation, indicating a delay in the preimplantation embryo development, and with increased expression of GATA3, an inhibitor of placentation. These results support that age and the metabolic syndrome reduce fertility through mechanisms which are present at conception or very early in pregnancy.

Age and Red Blood Cell Parameters Mainly Explain the Differences Between HbA1c and Glycemic Management Indicator Among Patients With Type 1 Diabetes Using Intermittent Continuous Glucose Monitoring.

BACKGROUND: Glycated hemoglobin (HbA1c) is the gold standard to assess glycemic control in patients with diabetes. Glucose management indicator (GMI), a metric generated by continuous glucose monitoring (CGM), has been proposed as an alternative to HbA1c, but the two values may differ, complicating clinical decision-making. This study aimed to identify the factors that may explain the discrepancy between them. METHODS: Subjects were patients with type 1 diabetes, with one or more HbA1c measurements after starting the use of the Freestyle Libre 2 intermittent CGM, who shared their data with the center on the Libreview platform. The 14-day glucometric reports were retrieved, with the end date coinciding with the date of each HbA1c measurement, and those with sensor use ≥70% were selected. Clinical data prior to the start of CGM use, glucometric data from each report, and other simultaneous laboratory measurements with HbA1c were collected. RESULTS: A total of 646 HbA1c values and their corresponding glucometric reports were obtained from 339 patients. The absolute difference between HbA1c and GMI was <0.3% in only 38.7% of cases. Univariate analysis showed that the HbA1c-GMI value was associated with age, diabetes duration, estimated glomerular filtration rate, mean corpuscular volume (MCV), red cell distribution width (RDW), and time with glucose between 180 and 250 mg/dL. In a multilevel model, only age and RDW, positively, and MCV, negatively, were correlated to HbA1c-GMI. CONCLUSION: The difference between HbA1c and GMI is clinically relevant in a high percentage of cases. Age and easily accessible hematological parameters (MCV and RDW) can help to interpret these differences.

Age, Origin and Functional Study of the Prevalent LDLR Mutation Causing Familial Hypercholesterolaemia in Gran Canaria.

The p.(Tyr400_Phe402del) mutation in the LDL receptor (LDLR) gene is the most frequent cause of familial hypercholesterolaemia (FH) in Gran Canaria. The aim of this study was to determine the age and origin of this prevalent founder mutation and to explore its functional consequences. For this purpose, we obtained the haplotypic information of 14 microsatellite loci surrounding the mutation in one homozygous individual and 11 unrelated heterozygous family trios. Eight different mutation carrier haplotypes were identified, which were estimated to originate from a common ancestral haplotype 387 (110-1572) years ago. This estimation suggests that this mutation happened after the Spanish colonisation of the Canary Islands, which took place during the fifteenth century. Comprehensive functional studies of this mutation showed that the expressed LDL receptor was retained in the endoplasmic reticulum, preventing its migration to the cell surface, thus allowing us to classify this LDLR mutation as a class 2a, defective, pathogenic variant.

25OHVitamin D Levels in a Canarian Pediatric Population with and without Type 1 Diabetes: The Role of Acidosis.

The role of Vitamin D in the development of type 1 diabetes (T1D) is controversial. The Canary Islands have the highest incidence of childhood-onset T1D in Spain and one of the highest in Europe. We aimed to evaluate 25OHVitamin D concentrations in a Canarian pediatric population, to assess the existence of seasonal variation, to study their association with T1D, and to evaluate the role of acidosis in its levels. In a retrospective, case-control study, we obtained data from 146 T1D patients (<15 years of age) and 346 control children; 25OHVitamin D concentrations were assessed in serum by automatic ChemiLuminescence ImmunoAssay technology. We found significantly higher 25OHVitamin D levels in the summer and autumn months and an inverse correlation between T1D and age; 25OHVitamin D sufficiency was similar in both groups (44.5% vs. 45.1%), with significant differences in the percentage of patients presenting vitamin D deficiency (11.6% (T1D) vs. 16.4% (controls)). When stratified according to the presence of ketoacidosis at sampling, only patients with acidosis showed lower 25OHVitamin D concentrations than controls. Despite its subtropical geographic location, Vitamin D deficiency is frequent in children in Gran Canaria, and 25OHVitamin D concentrations show seasonal variation. After adjusting for acidosis, no differences were found between children with and without T1D.

Quality, Usability, and Effectiveness of mHealth Apps and the Role of Artificial Intelligence: Current Scenario and Challenges.

The use of artificial intelligence (AI) and big data in medicine has increased in recent years. Indeed, the use of AI in mobile health (mHealth) apps could considerably assist both individuals and health care professionals in the prevention and management of chronic diseases, in a person-centered manner. Nonetheless, there are several challenges that must be overcome to provide high-quality, usable, and effective mHealth apps. Here, we review the rationale and guidelines for the implementation of mHealth apps and the challenges regarding quality, usability, and user engagement and behavior change, with a special focus on the prevention and management of noncommunicable diseases. We suggest that a cocreation-based framework is the best method to address these challenges. Finally, we describe the current and future roles of AI in improving personalized medicine and provide recommendations for developing AI-based mHealth apps. We conclude that the implementation of AI and mHealth apps for routine clinical practice and remote health care will not be feasible until we overcome the main challenges regarding data privacy and security, quality assessment, and the reproducibility and uncertainty of AI results. Moreover, there is a lack of both standardized methods to measure the clinical outcomes of mHealth apps and techniques to encourage user engagement and behavior changes in the long term. We expect that in the near future, these obstacles will be overcome and that the ongoing European project, Watching the risk factors (WARIFA), will provide considerable advances in the implementation of AI-based mHealth apps for disease prevention and health promotion.

Short-term evaluation of renal markers in overweight adult cats.

BACKGROUND: Obesity has been proposed as an independently risk factor for chronic kidney disease (CKD) in people, but its role in feline kidney function is unknown. OBJECTIVE: Obesity has been proposed as an independent risk factor for chronic kidney disease (CKD) in people, but its role in feline kidney function is unknown. This study prospectively evaluated the effect of overweight on the concentration of symmetric dimethylarginine (SDMA) and creatinine in a cohort of healthy cats. METHODS: Forty healthy adult cats were included, 14 with a body condition score (BCS) = 5 and 26 with a BCS > 5. Cats were examined every 6 months, for up to 12 months. SDMA and creatinine were measured at baseline and follow-up. RESULTS: No effect was found for time of follow-up (p = 0.072), overweight (p = 0.9442) or their interaction (p = 0.902) on SDMA, though a significant effect was found for age (p < 0.001) [older cats showing higher SDMA] and sex (p = 0.007) [male cats showing higher SDMA]. Regarding creatinine, no effect for time (p = 0.671), age (p = 0.061), overweight (p = 0.319) or the latter's interaction (p = 0.386) were found. CONCLUSIONS: In the short term, markers of renal function did not show an association with overweight. The role of obesity in feline kidney function still warrants further evaluation.

Towards a Multi-Omics of Male Infertility.

Infertility is a common problem affecting one in six couples and in 30% of infertile couples, the male factor is a major cause. A large number of genes are involved in spermatogenesis and a significant proportion of male infertility phenotypes are of genetic origin. Studies on infertility have so far primarily focused on chromosomal abnormalities and sequence variants in protein-coding genes and have identified a large number of disease-associated genes. However, it has been shown that a multitude of factors across various omics levels also contribute to infertility phenotypes. The complexity of male infertility has led to the understanding that an integrated, multi-omics analysis may be optimal for unravelling this disease. While there is a vast array of different factors across omics levels associated with infertility, the present review focuses on known factors from the genomics, epigenomics, transcriptomics, proteomics, metabolomics, glycomics, lipidomics, miRNomics, and integrated omics levels. These include: repeat expansions in AR, POLG, ATXN1, DMPK, and SHBG, multiple SNPs, copy number variants in the AZF region, disregulated miRNAs, altered H3K9 methylation, differential MTHFR, MEG3, PEG1, and LIT1 methylation, altered protamine ratios and protein hypo/hyperphosphorylation. This integrative review presents a step towards a multi-omics approach to understanding the complex etiology of male infertility. Currently only a few genetic factors, namely chromosomal abnormalities and Y chromosome microdeletions, are routinely tested in infertile men undergoing intracytoplasmic sperm injection. A multi-omics approach to understanding infertility phenotypes may yield a more holistic view of the disease and contribute to the development of improved screening methods and treatment options. Therefore, beside discovering as of yet unknown genetic causes of infertility, integrating multiple fields of study could yield valuable contributions to the understanding of disease development. Future multi-omics studies will enable to synthesise fragmented information and facilitate biomarker discovery and treatments in male infertility.

Ex vivo evaluation of adhesive strength and barrier effect of a novel treatment for esophagitis.

AIM: To investigate the mucoadhesive strength and barrier effect of Esophacare® (Atika Pharma SL, Las Palmas de Gran Canaria) in an ex vivo model of gastro-oesophageal reflux. METHODS: An ex vivo evaluation through the Falling Liquide Film Technique with porcine esophagi was performed, compared to a positive control (Ziverel®; Norgine, Amsterdam), after different washing periods with saline, acidified saline (pH 1.2) and acidified saline with pepsin (2000U/mL). RESULTS: The adhesive mean strength on the oesophageal mucosa of Esophacare was 94.7 (6.0)%, compared to 27.6 (19.1)% of the positive control (p<0.05). These results were homogeneous across the different washes and throughout the tissue. The area covered by 1mL of Esophacare, and its respective persistence after washing was also assessed, yielding a mean global persistence of 74.29 (19.7)% vs. 18.9 (12.3)% for the control (p<0.05). In addition, after 30min exposure to acidified saline with pepsin, Esophacare shows a protective effect on the oesophageal mucosa, detectable histologically: preserved integrity and structure of the apical layers was observed, as well as reduced permeability to the washing solution. CONCLUSIONS: Esophacare shows an adhesive strength close to 100%, irrespective of the washing solution applied or the oesophageal region studied. Histologically, it reduces the abrasive effects of the acidic solution on the oesophageal epithelium, reducing permeability to the washing solution. The results in this ex vivo model of gastro-oesophageal reflux disease (GERD) support its therapeutic potential.

Synthetic Patient Data Generation and Evaluation in Disease Prediction Using Small and Imbalanced Datasets.

The increasing prevalence of chronic non-communicable diseases makes it a priority to develop tools for enhancing their management. On this matter, Artificial Intelligence algorithms have proven to be successful in early diagnosis, prediction and analysis in the medical field. Nonetheless, two main issues arise when dealing with medical data: lack of high-fidelity datasets and maintenance of patient's privacy. To face these problems, different techniques of synthetic data generation have emerged as a possible solution. In this work, a framework based on synthetic data generation algorithms was developed. Eight medical datasets containing tabular data were used to test this framework. Three different statistical metrics were used to analyze the preservation of synthetic data integrity and six different synthetic data generation sizes were tested. Besides, the generated synthetic datasets were used to train four different supervised Machine Learning classifiers alone, and also combined with the real data. F1-score was used to evaluate classification performance. The main goal of this work is to assess the feasibility of the use of synthetic data generation in medical data in two ways: preservation of data integrity and maintenance of classification performance.

Impact of a Mediterranean diet, physical activity, body composition, and insulin delivery methods on metabolic control in children with type 1 diabetes.

Aims: To evaluate the synergistic impact of diet, lifestyle and technology on glycemic control in children with type 1 diabetes (T1D). Methods: This cross-sectional study included 112 randomly selected patients with T1D from Gran Canaria (median age 12 years; 51.8% female). The study collected data on height, weight, body composition (bioimpedance), age, disease duration, and method of insulin delivery. Physical activity was evaluated using the Krece questionnaire and an accelerometer (GENEActiv). Adherence to the Mediterranean diet was assessed using the KIDMED Quick Nutrition Test. Glycemic control was evaluated using HbA1c and the percentage of time in range. SPSS version 21 and RStudio were used for statistical analysis of the data. Stepwise linear regression analysis (backwards) was used to identify factors independently associated with metabolic control. Results: Insulin pump use, age and adherence to the Mediterranean diet were found to be significantly and independently associated with better glycemic control, whereas years with T1D was associated with worse HbA1c values. No relationship was found between body composition and physical activity measured by accelerometry or questionnaire. Conclusion: Adherence to the Mediterranean diet, insulin delivery methods, age, and number of years with T1D are important factors to consider in the management of T1D in children.

Addition of intermittently scanned continuous glucose monitoring to standard care in a cohort of pregnant women with type 1 diabetes: effect on glycaemic control and pregnancy outcomes.

AIMS/HYPOTHESIS: The aim of this study was to assess whether the addition of intermittently scanned continuous glucose monitoring (isCGM) to standard care (self-monitoring of blood glucose [SMBG] alone) improves glycaemic control and pregnancy outcomes in women with type 1 diabetes and multiple daily injections. METHODS: This was a multicentre observational cohort study of 300 pregnant women with type 1 diabetes in Spain, including 168 women using SMBG (standard care) and 132 women using isCGM in addition to standard care. In addition to HbA1c, the time in range (TIR), time below range (TBR) and time above range (TAR) with regard to the pregnancy glucose target range (3.5-7.8 mmol/l) were also evaluated in women using isCGM. Logistic regression models were performed for adverse pregnancy outcomes adjusted for baseline maternal characteristics and centre. RESULTS: The isCGM group had a lower median HbA1c in the second trimester than the SMBG group (41.0 [IQR 35.5-46.4] vs 43.2 [IQR 37.7-47.5] mmol/mol, 5.9% [IQR 5.4-6.4%] vs 6.1% [IQR 5.6-6.5%]; p=0.034), with no differences between the groups in the other trimesters (SMBG vs isCGM: first trimester 47.5 [IQR 42.1-54.1] vs 45.9 [IQR 39.9-51.9] mmol/mol, 6.5% [IQR 6.0-7.1%] vs 6.4% [IQR 5.8-6.9%]; third trimester 43.2 [IQR 39.9-47.5] vs 43.2 [IQR 39.9-47.5] mmol/mol, 6.1% [IQR 5.8-6.5%] vs 6.1% [IQR 5.7-6.5%]). The whole cohort showed a slight increase in HbA1c from the second to the third trimester, with a significantly higher rise in the isCGM group than in the SMBG group (median difference 2.2 vs 1.1 mmol/mol [0.2% vs 0.1%]; p=0.033). Regarding neonatal outcomes, newborns of women using isCGM were more likely to have neonatal hypoglycaemia than newborns of non-sensor users (27.4% vs 19.1%; ORadjusted 2.20 [95% CI 1.14, 4.30]), whereas there were no differences between the groups in large-for-gestational-age (LGA) infants (40.6% vs 45.1%; ORadjusted 0.73 [95% CI 0.42, 1.25]), Caesarean section (57.6% vs 48.8%; ORadjusted 1.33 [95% CI 0.78, 2.27]) or prematurity (27.3% vs 24.8%; ORadjusted 1.05 [95% CI 0.55, 1.99]) in the adjusted models. A sensitivity analysis in pregnancies without LGA infants or prematurity also showed that the use of isCGM was associated with a higher risk of neonatal hypoglycaemia (non-LGA: ORadjusted 2.63 [95% CI 1.01, 6.91]; non-prematurity: ORadjusted 2.52 [95% CI 1.12, 5.67]). For isCGM users, the risk of delivering an LGA infant was associated with TIR, TAR and TBR in the second trimester in the logistic regression analysis. CONCLUSIONS/INTERPRETATION: isCGM use provided an initial improvement in glycaemic control that was not sustained. Furthermore, offspring of isCGM users were more likely to have neonatal hypoglycaemia, with similar rates of macrosomia and prematurity to those of women receiving standard care.

Impact of anxiety, depression and disease-related distress on long-term glycaemic variability among subjects with Type 1 diabetes mellitus.

BACKGROUND: Anxiety, depression, and disease-related distress are linked to worse overall glycaemic control, in terms of HbA1c. This study was aimed to evaluate whether traits of these emotional disorders are associated with long-term glycaemic variability in subjects with Type 1 diabetes. METHODS: Longitudinal retrospective study. Six-year HbA1c data (2014-2019) from 411 subjects with Type 1 diabetes who had participated in a previous study to design a diabetes-specific quality of life questionnaire in the year 2014 were included. Scores for Spanish versions of the Hospital Anxiety and Depression Scale (HADS) and Problem Areas in Diabetes (PAID) scale were obtained at baseline, along with sociodemographic and clinical data. Long-term glycaemic variability was measured as the coefficient of variation of HbA1c (HbA1c-CV). The association between HADS and PAID scores and HbA1c-CV was analysed with Spearman correlations and multiple regression models, both linear and additive, including other covariates (age, sex, diabetes duration time, type of treatment, baseline HbA1c, use of anxiolytic or antidepressant drugs, education level and employment status). RESULTS: Scores of depression, anxiety and distress were positively and significantly correlated to HbA1c-CV in univariate analyses. Multiple regression study demonstrated an independent association only for diabetes distress score (p < 0.001). Age, diabetes duration time, baseline HbA1c, education level and employment status were also significantly associated with HbA1c-CV. However, when subjects were analyzed separately in two age groups, distress scores were associated with HbA1c-CV only among those aged 25 years or older, while anxiety scores, but not distress, were associated with HbA1c-CV among those younger than 25 years. CONCLUSIONS: Psychological factors, particularly disease-related distress and anxiety, are associated with long-term glycaemic variability in subjects with Type 1 diabetes.

Grandmaternal exercise improves metabolic health of second-generation offspring.

OBJECTIVE: A major factor in the growing world-wide epidemic of obesity and type 2 diabetes is the increased risk of transmission of metabolic disease from obese mothers to both first (F1) and second (F2) generation offspring. Fortunately, recent pre-clinical studies demonstrate that exercise before and during pregnancy improves F1 metabolic health, providing a potential means to disrupt this cycle of disease. Whether the beneficial effects of maternal exercise can also be transmitted to the F2 generation has not been investigated. METHODS: C57BL/6 female mice were fed a chow or high-fat diet (HFD) and housed in individual cages with or without running wheels for 2 wks before breeding and during gestation. Male F1 offspring were sedentary and chow-fed, and at 8-weeks of age were bred with age-matched females from untreated parents. This resulted in 4 F2 groups based on grandmaternal treatment: chow sedentary; chow trained; HFD sedentary; HFD trained. F2 were sedentary and chow-fed and studied up to 52-weeks of age. RESULTS: We find that grandmaternal exercise improves glucose tolerance and decreases fat mass in adult F2 males and females, in the absence of any treatment intervention of the F1 after birth. Grandmaternal exercise also improves F2 liver metabolic function, including favorable effects on gene and miRNA expression, triglyceride concentrations and hepatocyte glucose production. CONCLUSION: Grandmaternal exercise has beneficial effects on the metabolic health of grandoffspring, demonstrating an important means by which exercise during pregnancy could help reduce the worldwide incidence of obesity and type 2 diabetes.

Cost-effectiveness of multicomponent interventions in type 2 diabetes mellitus in a cluster randomised controlled trial: the INDICA study.

OBJECTIVE: To analyse the cost-effectiveness of multicomponent interventions designed to improve outcomes in type 2 diabetes mellitus (T2DM) in primary care in the Canary Islands, Spain, within the INDICA randomised clinical trial, from the public health system perspective. DESIGN: An economic evaluation was conducted for the within-trial period (2 years) comparing the four arms of the INDICA study. SETTING: Primary care in the Canary Islands, Spain. PARTICIPANTS: 2334 patients with T2DM without complications were included. INTERVENTIONS: Interventions for patients (PTI), for primary care professionals (PFI), for both (combined intervention arm for patients and professionals, CBI) and usual care (UC) as a control group. OUTCOMES: The main outcome was the incremental cost per quality-adjusted life-years (QALY). Only the intervention and the healthcare costs were included. ANALYSIS: Multilevel models were used to estimate results, and to measure the size and significance of incremental changes. Missed values were treated by means of multiple imputations procedure. RESULTS: There were no differences between arms in terms of costs (p=0.093), while some differences were observed in terms of QALYs after 2 years of follow-up (p=0.028). PFI and CBI arms were dominated by the other two arms, PTI and UC. The differences between the PTI and the UC arms were very small in terms of QALYs, but significant in terms of healthcare costs (p=0.045). The total cost of the PTI arm (€2571, 95% CI €2317 to €2826) was lower than the cost in the UC arm (€2750, 95% CI €2506 to €2995), but this difference did not reach statistical significance. Base case estimates of the incremental cost per QALY indicate that the PTI strategy was the cost-effective option. CONCLUSIONS: The INDICA intervention designed for patients with T2DM and families is likely to be cost-effective from the public healthcare perspective. A cost-effectiveness model should explore this in the long term. TRIAL REGISTRATION NUMBER: NCT01657227.