Endocannabinoid signaling in brain diseases: Emerging relevance of glial cells.

The discovery of cannabinoid receptors as the primary molecular targets of psychotropic cannabinoid Δ9 -tetrahydrocannabinol (Δ9 -THC) in late 1980s paved the way for investigations on the effects of cannabis-based therapeutics in brain pathology. Ever since, a wealth of results obtained from studies on human tissue samples and animal models have highlighted a promising therapeutic potential of cannabinoids and endocannabinoids in a variety of neurological disorders. However, clinical success has been limited and major questions concerning endocannabinoid signaling need to be satisfactorily addressed, particularly with regard to their role as modulators of glial cells in neurodegenerative diseases. Indeed, recent studies have brought into the limelight diverse, often unexpected functions of astrocytes, oligodendrocytes, and microglia in brain injury and disease, thus providing scientific basis for targeting glial cells to treat brain disorders. This Review summarizes the current knowledge on the molecular and cellular hallmarks of endocannabinoid signaling in glial cells and its clinical relevance in neurodegenerative and chronic inflammatory disorders.

Association between inadequate weight gain according to the institute of medicine 2009 guidelines and pregnancy outcomes in women with thyroid disorders.

PURPOSE: Gestational weight gain (GWG) is an important contributor to pregnancy outcomes in the general obstetric population and different subgroups. The corresponding information in women with thyroid conditions is limited. We aimed to evaluate the relationship between GWG according to institute of medicine (IOM) and pregnancy outcomes in women with thyroid disorders. METHODS: We performed a retrospective analysis of 620 pregnant women either treated with levothyroxine (N = 545) or attended because of hyperthyroidism during pregnancy (N = 75). RESULTS: The associations between GWG according to IOM and pregnancy outcomes were present both in women treated with thyroid hormone and women followed by hyperthyroidism, most of them related to the fetal outcomes. In women treated with levothyroxine, insufficient GWG was associated with gestational diabetes mellitus (GDM) (odds ratio (OR) 2.32, 95% confidence interval (CI) 1.18, 4.54), preterm birth (OR 2.31, 95% CI 1.22, 4.36), small-for-gestational age newborns (OR 2.38, 95% CI 1.09, 5.22) and respiratory distress (OR 6.89, 95% CI 1.46, 32.52). Excessive GWG was associated with cesarean delivery (OR 1.66, 95% CI 1.10, 2.51) and macrosomia (OR 2.75, 95% CI 1.38, 5.49). Large-for-gestational age newborns were associated with both insufficient GWG (OR 0.25, 95% CI 0.11, 0.58) and excessive GWG (OR 1.80, 95% CI 1.11, 2.92). In women followed by hyperthyroidism, excessive GWG was associated with large-for-gestational age newborns (OR 5.56, 95% CI 1.03, 29.96). CONCLUSION: GWG according to IOM is associated with pregnancy outcomes both in women treated with thyroid hormone and women followed by hyperthyroidism.

Δ9 -Tetrahydrocannabinol promotes oligodendrocyte development and CNS myelination in vivo.

Δ9 -Tetrahydrocannabinol (THC), the main bioactive compound found in the plant Cannabis sativa, exerts its effects by activating cannabinoid receptors present in many neural cells. Cannabinoid receptors are also physiologically engaged by endogenous cannabinoid compounds, the so-called endocannabinoids. Specifically, the endocannabinoid 2-arachidonoylglycerol has been highlighted as an important modulator of oligodendrocyte (OL) development at embryonic stages and in animal models of demyelination. However, the potential impact of THC exposure on OL lineage progression during the critical periods of postnatal myelination has never been explored. Here, we show that acute THC administration at early postnatal ages in mice enhanced OL development and CNS myelination in the subcortical white matter by promoting oligodendrocyte precursor cell cycle exit and differentiation. Mechanistically, THC-induced-myelination was mediated by CB1 and CB2 cannabinoid receptors, as demonstrated by the blockade of THC actions by selective receptor antagonists. Moreover, the THC-mediated modulation of oligodendroglial differentiation relied on the activation of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, as mTORC1 pharmacological inhibition prevented the THC effects. Our study identifies THC as an effective pharmacological strategy to enhance oligodendrogenesis and CNS myelination in vivo.

Both glycaemic control and insulin dose during pregnancy in women with type 1 diabetes are associated with neonatal anthropometric measures and placental weight.

BACKGROUND: To investigate longitudinal associations of maternal glucose/HbA1c and insulin dose with birthweight-related outcomes in women with type 1 diabetes. METHODS: We performed a cohort study including 473 pregnant women with type 1 diabetes with singleton pregnancies. We investigated maternal self-monitored blood glucose (SMBG, mmol/L), HbA1c (%, mmol/mol) and insulin dose (IU/kg/day) in the three trimesters as potential independent variables, while adjusting for potential confounders. Outcomes of interest were birthweight, birthweight SD score, neonatal length, weight/length index, ponderal index and placental weight. Multiple linear regression analysis was performed with separate analyses for SMBG and HbA1c . RESULTS: Maternal glucose and insulin dose were independently associated with birthweight-related outcomes. In the main analysis, in the first trimester most associations were positive for insulin dose, in the second the associations were positive for glucose and inverse for insulin while in the third there were no associations. Most sensitivity analyses produced consistent results. In a sensitivity analysis splitting the first trimester in two periods, positive associations of maternal insulin with birthweight-related outcomes were observed in weeks 0+ to 6+. CONCLUSIONS: Early in pregnancy in women with type 1 diabetes, maternal insulin dose is positively associated with birthweight-related outcomes, whereas in the second trimester, a positive association with SMBG emerges and the association with maternal insulin becomes inverse. If confirmed in other cohorts, these results would have implications in the management of women with type 1 diabetes.

Intensive Insulin Therapy (Basal-Bolus).

BACKGROUND: Intensive insulin therapy (IIT) aims at achieving near-normal glycemic control and usually uses a basal-bolus (BB) schema to mimic physiologic insulin secretion. AREAS OF UNCERTAINTY: The treatment burden of IIT should be outweighed by improved glycemic control and reduction of chronic complications, but reviews summarizing the effects of IIT in subjects with T1DM and T2DM in glycated hemoglobin, hypoglycemia, insulin doses, and weight are limited. DATA SOURCES: We performed a PubMed search to identify relevant randomized control trials (RCTs) comparing IIT and conventional insulin treatment in T1DM and T2DM subjects and addressing glycated hemoglobin, hypoglycemia, insulin requirements, and weight. THERAPEUTIC ADVANCES: We have identified 11 RCTs in T1DM subjects, published years ago and very heterogenous in design. Throughout the studies there was a consistent superiority of IIT in glycated hemoglobin reduction, a higher rate of severe hypoglycemia and more weight gain in the IIT group without a clear effect on insulin doses. We have identified 2 RCTs in T2DM subjects, only one of them using a definite BB schema in the IIT group. IIT induced more hypoglycemia and better HbA1c, but not more weight gain. CONCLUSIONS: IIT is the best option for treatment of subjects with T1DM in HbA1c reduction with a cost in the rate of hypoglycemia and weight gain. In subjects with T2DM, IIT also yields improvement in HbA1c versus conventional treatment, also at the cost of more hypoglycemic episodes, but not of higher weight gain. RCT treatment arms did not only differ in the insulin schema, but also in treatment goals, therapeutic education, and frequency of clinical visits among other characteristics. However, most evidence was gained using a BB insulin schema in the intensive arm and it is likely that the insulin schema had a relevant contribution in the results.

Quality of malaria services offered in public health facilities in three provinces of Mozambique: a cross-sectional study.

BACKGROUND: Fever associated with malaria is the leading cause of health care-seeking in Mozambique, yet there is limited evidence on the quality of malaria case management. This study evaluated the quality of malaria service provision offered in public health facilities in Mozambique. METHODS: A cross-sectional assessment was conducted in April-May 2018 in three provinces of Mozambique: Maputo Province (low malaria burden), Cabo Delgado (high), and Zambézia (high). The study included all secondary and tertiary facilities and a random sample of primary facilities in each province. Data collection included exit interviews and re-examinations of 20 randomly selected outpatient service patients, interviews with up to five health care providers and the health facility director, a stockroom inventory and routine data abstraction. RESULTS: A total of 319 health care providers and 1840 patients from 117 health facilities were included. Of these, 1325 patients (72%) had suspected malaria (fever/history of fever) and 550 (30%) had febrile, confirmed malaria with the highest burden in Cabo Delgado (43%), followed by Zambézia (34%) and Maputo Province (2%). Appropriate management of malaria cases, defined as testing malaria suspects and treating confirmed cases with the correct dose of anti-malarial, was highest in Zambézia and Cabo Delgado where 52% (95% CI 42-62) and 49% (42-57) of febrile malaria cases were appropriately managed, respectively. Only 14% (5-34) of febrile cases in Maputo Province were appropriately managed. The biggest gap in the malaria case management pathway was failure to test febrile patients, with only 46% of patients with this indication tested for malaria in Maputo Province. Additionally, anti-malarial treatment of patients with a negative malaria test result was common, ranging from 8% (2-23) in Maputo Province to 22% (14-32) of patients with a negative test in Zambézia. Only 58-62% of patients prescribed an anti-malarial correctly recited dosing instructions. Provider training and malaria knowledge was low outside of Zambézia and supervision rates were low in all provinces. Factors associated with correct case management varied by province and included patient age, facility type, treatment and testing availability, supervision, and training. CONCLUSION: These findings underscore the need to strengthen provider testing of all patients with fever, provider adherence to negative test results, and effective counselling of patients across epidemiological settings in Mozambique.

Efficacy of a hyperglycemia treatment program in a Vascular Surgery Department supervised by Endocrinology. / Eficacia de un programa de tratamiento de la hiperglucemia en un Servicio de Cirugía Vascular supervisado por Endocrinología.

BACKGROUND: The aim of this study was to evaluate the strategy and efficacy of a hyperglycemia treatment program supervised by Endocrinology. METHODS: All patients with type 2 diabetes hospitalized at the vascular surgery department over a 12 month period were retrospectively reviewed. Clinical characteristics and hyperglycemia treatment during hospitalization, at discharge and 2-6 month after discharge were collected. Glycemic control was assessed using capillary blood glucose profiles and HbA1c at admission and 2-6 months post-discharge. RESULTS: A total of 140 hospitalizations of 123 patients were included. The protocol to choose the insulin regimen was applied in 96.4% of patients (22.8% correction dose, 23.6% basal-correction dose and 50% basal-bolus-correction dose [BBC]). Patients with BBC had higher HbA1c (7.7±1.5% vs. 6.7 ±0.8%; P<.001) and mean glycemia on the first day of hospitalization (184.4±59.2 vs. 140.5±31.4mg/dl; P<.001). Mean blood glucose was reduced to 162.1±41.8mg/dl in the middle and 160.8±43.3mg/dl in the last 24h of hospitalization in patients with BBC (P=.007), but did not change in the remaining patients. In 22.1% patients with treatment changes performed at discharge, HbA1c decreased from 8.2±1.6 to 6.8±1.6% at 2-6 months post-discharge (P=.019). CONCLUSIONS: The hyperglycemia treatment protocol applied by an endocrinologist in the hospital, allows the identification of the appropriate therapy and the improvement of the glycemic control during hospitalization and discharge, supporting its efficacy in clinical practice.

Blockade of monoacylglycerol lipase inhibits oligodendrocyte excitotoxicity and prevents demyelination in vivo.

The endocannabinoids 2-araquidonoylglycerol (2-AG) and anandamide (AEA) are bioactive lipids crucially involved in the regulation of brain function in basal and pathological conditions. Blockade of endocannabinoid metabolism has emerged as a promising therapeutic strategy for inflammatory diseases of the central nervous system, including myelin disorders such as multiple sclerosis. Nevertheless, the biological actions of endocannabinoid degradation inhibitors in oligodendrocytes and white matter tracts are still ill defined. Here we show that the selective monoacylglycerol lipase (MAGL) inhibitor JZL184 suppressed cell death by mild activation of AMPA receptors in oligodendrocytes in vitro, an effect that was mimicked by MAGL substrate 2-AG and by the second major endocannabinoid AEA, in a concentration-dependent manner, whereas inhibition of the AEA metabolizing enzyme fatty acid amide hydrolase with URB597 was devoid of effect. Pharmacological experiments suggested that oligodendrocyte protection from excitotoxicity resulting from MAGL blockade involved the activation of cannabinoid CB1 receptors and the reduction of AMPA-induced cytosolic calcium overload, mitochondrial membrane depolarization, and production of reactive oxygen species. Administration of JZL184 under a therapeutic regimen decreased clinical severity, prevented demyelination, and reduced inflammation in chronic experimental autoimmune encephalomyelitis. Furthermore, MAGL inactivation robustly preserved myelin integrity and suppressed microglial activation in the cuprizone-induced model of T-cell-independent demyelination. These findings suggest that MAGL blockade may be a useful strategy for the treatment of immune-dependent and -independent damage to the white matter.

The Hybrid Closed-Loop System Tandem t:slim X2™ with Control-IQ Technology: Expert Recommendations for Better Management and Optimization.

Technological advances in the management of diabetes, especially type 1 diabetes (T1D), have played a main role in significantly improving glycemic control of these patients in recent years. Undoubtedly, the most important advance has been the commercialization of hybrid closed-loop systems (HCL). Their effectiveness places them in the different guidelines from scientific societies as the gold standard for the treatment of people with T1D. However, obtaining the maximum performance from these systems requires a degree of expertise from the professionals who care for these patients. Specifically, the Tandem X2:slim with Control-IQ technology system, due to its features and configuration options and adjustments, allows T1D patients to better adapt the management of diabetes to multiple circumstances in their day-to-day life. It is necessary, however, to follow a systematic process to start the system and also for the subsequent follow-up, which allows its optimization in the shortest possible time. This expert recommendation reviews the main features of this HCL system, suggesting how to implement it and optimize its use after gaining experience treating many patients.

Gestational weight gain in women with type 1 and type 2 diabetes mellitus is related to both general and diabetes-related clinical characteristics.

PURPOSE: To assess predictors of gestational weight gain (GWG), according to the Institute of Medicine (IOM) 2009, in women with type 1 and type 2 diabetes. METHODS: This was a retrospective cohort study conducted at a tertiary center. GWG based on the IOM was assessed both uncorrected and corrected for gestational age. General and diabetes-related clinical characteristics were analyzed as predictors. RESULTS: We evaluated 633 pregnant women with type 1 and type 2 diabetes. GWG uncorrected for gestational age was inadequate (iGWG) in 20.4%, adequate in 37.1%, and excessive (eGWG) in 42.5% of the women. Predictors included general (height, prepregnancy body mass index category, and multiple pregnancy) and diabetes-related clinical characteristics. Neuropathy and follow-up length were associated with iGWG (odds ratio (OR) 3.00, 95% CI 1.22-7.37; OR 0.92, 95% CI 0.86-0.97, respectively), while pump use and third-trimester insulin dose were associated with eGWG (OR 1.68, 95% CI 1.07-2.66; OR 3.64, 95% CI 1.88-7.06, respectively). Independent predictors for corrected GWG and sensitivity analyses also included general and diabetes-related clinical characteristics. CONCLUSION: In this cohort of women with type 1 and type 2 diabetes, non-adequate GWG was common, mainly due to eGWG, and associated clinical characteristics were both general and diabetes-related. Current clinical care of these women during pregnancy may favor weight gain.

Real-world safety and effectiveness of dapagliflozin in people living with type 1 diabetes in Spain: The Dapa-ON multicenter retrospective study.

OBJECTIVE: To assess real-world safety and effectiveness of dapagliflozin in people living with type 1 diabetes mellitus (T1DM). METHODS: We conducted a multicenter retrospective study in Spain including data from 250 people living with T1DM receiving dapagliflozin as add-on therapy to insulin (80.8 % on-label use). The number of diabetic ketoacidosis (DKA) events was calculated over a 12-month follow-up (primary outcome). Changes in body weight, HbA1c, total daily insulin dose, and continuous glucose monitoring (CGM) metrics from baseline (at dapagliflozin prescription) to 12 months were also evaluated. RESULTS: A total of five DKA events (2.4 % [95 % CI 0.3;4.5] were reported in patients with a 12-month follow-up, n = 207): two events related to insulin pump malfunction, two events related to concomitant illnesses, and one event related to insulin dose omission. DKA events were more frequent among insulin pump users than among participants on multiple daily injections (7.7 % versus 1.2 %). Four of the reported DKA events occurred within the first six months after initiation of dapagliflozin. No deaths or persistent sequelae due to DKA were reported. No severe hypoglycemia episodes were reported. Significant reductions in mean body weight (-3.3 kg), HbA1c (-0.6 %), and total daily insulin dose (-8.6 %), P < 0.001, were observed 12 months after dapagliflozin prescription. Significant improvements in TIR (+9.3 %), TAR (-7.2 %), TBR (-2.5 %), and coefficient of variation (-5.1 %), P < 0.001, were also observed in the subgroup of patients with available CGM data. Finally, an improvement in urinary albumin-to-creatinine ratio (UACR) was found among participants with UACR ≥ 30 mg/g at baseline (median decrease of 99 mg/g in UACR, P = 0.001). CONCLUSION: The use of dapagliflozin in people living with T1DM has an appropriate safety profile after careful selection of participants and implementation of strategies to reduce the risk of DKA (i.e., prescribed according to the recommendations of the European Medicines Agency), and also leads to clinical improvements in this population.

A Multicenter Prospective Evaluation of the Benefits of Two Advanced Hybrid Closed-Loop Systems in Glucose Control and Patient-Reported Outcomes in a Real-world Setting.

OBJECTIVE: Advanced hybrid closed-loop systems (AHCL) have been shown to improve glycemic control and patient-reported outcomes in type 1 diabetes. The aim was to analyze the outcomes of two commercially available AHCL in real life. RESEARCH DESIGN AND METHODS: A prospective study was performed, including adolescents and adults with type 1 diabetes, AHCL naïve, from 14 centers, who initiated the use of MM780G with SmartGuard or Tandem t:slimX2 with Control-IQ. Baseline and 3-month evaluations were performed, assessing HbA1c, time in different glycemic ranges, and patient-reported outcomes. The primary outcome was the between-group time in range 70-180 mg/dL difference from beginning to end of follow-up. RESULTS: One hundred fifty participants were included, with 75 initiating each system (age: 39.9 ± 11.4 years [16-72]; 64% female; diabetes duration: 21.6 ± 11.9 years). Time in range increased from 61.53 ± 14.01% to 76.17 ± 9.48% (P < 0.001), with no between-group differences (P = 0.591). HbA1c decreased by 0.56% (95% CI 0.44%, 0.68%) (6 mmol/mol, 95% CI 5, 7) (P < 0.001), from 7.43 ± 1.07% to 6.88 ± 0.60% (58 ± 12 to 52 ± 7 mmol/mol) in the MM780G group, and from 7.14 ± 0.70% to 6.56 ± 0.53% (55 ± 8 to 48 ± 6 mmol/mol) in the Control-IQ group (both P < 0.001 to baseline, P = 0.819 between groups). No superiority of one AHCL over the other regarding fear of hypoglycemia or quality of life was found. Improvement in diabetes-related distress was higher in Control-IQ users (P = 0.012). Sleep quality was improved (PSQI: from 6.94 ± 4.06 to 6.06 ± 4.05, P = 0.004), without differences between systems. Experience with AHCL, evaluated by the INSPIRE measures, exceeded the expectations. CONCLUSIONS: The two AHCL provide significant improvement in glucose control and satisfaction, with no superiority of one AHCL over the other.

Cytosolic zinc accumulation contributes to excitotoxic oligodendroglial death.

Dyshomeostasis of cytosolic Zn(2+) is a critical mediator of neuronal damage during excitotoxicity. However, the role of this cation in oligodendrocyte pathophysiology is not well understood. The current study examined the contribution of Zn(2+) deregulation to oligodendrocyte injury mediated by AMPA receptors. Oligodendrocytes loaded with the Zn(2+)-selective indicator FluoZin-3 responded to mild stimulation of AMPA receptors with fast cytosolic Zn(2+) rises that resulted from intracellular release, as they were not blocked by the extracellular Zn(2+) chelator Ca-EDTA. Pharmacological experiments suggested that AMPA-induced Zn(2+) mobilization depends on cytosolic Ca(2+) accumulation, arises from mitochondria and protein-bound pools, and is triggered by mechanisms that do not involve the generation of reactive oxygen species. Moreover, intracellular Zn(2+) rises resulting from AMPA receptor activation seem to be promoted by Ca(2+)-dependent cytosolic acidification. Addition of the cell-permeable Zn(2+) chelator TPEN significantly reduced mitochondrial membrane depolarization, reactive oxygen species production, and cell death by sub-maximal activation of AMPA receptors both in vitro and in situ, suggesting that Zn(2+) deregulation is an important mediator of oligodendrocyte excitotoxicity. These data provide evidence that strategies aimed at maintaining Zn(2+) homeostasis may be useful for the treatment of disorders in which excitotoxicity is an important trigger of oligodendroglial death.

Efficacy, Safety, and Satisfaction with the Accu-Chek Insight with Diabeloop Closed-Loop System in Subjects with Type 1 Diabetes: A Multicenter Real-World Study.

Aim: To evaluate the efficacy, safety and satisfaction of the closed-loop system Accu-Chek® Insight with Diabeloop™ (DBLG1™) in adults with type 1 diabetes (T1D) in real-world conditions. Methods: Patients with T1D using DBLG1 for at least 3 months were included. Glucometric parameters were analyzed at baseline, 1, 2, and 3 months after starting DBLG1. HbA1c was measured before and at 3 months. Technical issues and acute complications were recorded and patients completed a satisfaction questionnaire. Results: Sixty-two patients were included (43 women; age 44.2 ± 11 years; diabetes duration 24.6 ± 12 years; 40 used flash and 22 continuous glucose monitoring (CGM); 45 were on insulin pump and 17 on multiple daily injections). A significant improvement was observed in the CGM-derived glucose metrics early in the first month: Time in range (%TIR) 70-180 mg/dL (54.86 ± 17 vs. 72.23 ± 10.11); time above range level 1 (%TAR1) 180-250 mg/dL (26.26 ± 13.3 vs. 19.48 ± 6.78), time above range level 2 (%TAR2) > 250 mg/dL (12.02 ± 13.09 vs. 6.14 ± 5.23), time below range level 1 (%TBR 1) 54-70 mg/dL (5.73 ± 11.5 vs. 1.67 ± 1.3), time below range level 2 (%TBR2) < 54 mg/dL (1.18 ± 1.97 vs.0.44 ± 0.49), %CV (38.66 ± 7.53 vs. 29.63 ± 3.74), median glucose (168.57 ± 36 mg/dL vs. 154.63 ± 17.55 mg/dL), and %GMI (7.37 ± 0.91 vs. 7.02 ± 0.42). Also, HbA1c decreased significantly (7.45% ± 1.05% vs. 6.95% ± 0.7%). No acute complications or serious adverse events occurred. Similar improvement was observed regardless of prior therapy or the glucose monitoring system used. Three patients discontinued DBLG1 and 21 experienced technical issues. Overall, patient satisfaction was high. Adjustments of the settings were modified in general in the direction of greater aggressiveness. Conclusions: A significant improvement in glycemic control without serious adverse events and a high degree of patient satisfaction were observed in this first real-world study evaluating the closed-loop system, Accu-Chek Insight with Diabeloop.

Spanish Consensus on the Use of Intermittently Scanned Continuous Glucose Monitoring in the Management of Patients With Insulin Therapy: The MONITOR Project.

BACKGROUND: Continuous glucose monitoring (CGM) systems are increasingly being adopted as an alternative or adjunct to self-monitoring of blood glucose (SMBG) by patients receiving insulin therapy. However, the available evidence on the role of intermittently scanned CGM or flash CGM (isCGM) remains limited. This consensus aims to evaluate the degree of agreement among Spanish experts on the role of isCGM in the evaluation of glycemic variability, reduction of glycosylated hemoglobin (HbA1c) levels, and selection and adjustment of insulin therapy. METHODS: Delphi methodology was used to achieve consensus in two survey rounds. A total of 431 Spanish endocrinologists participated in the first round of a 34-item questionnaire survey on isCGM and 427 participated in the second round. Any disagreement was resolved in round 2. RESULTS: Consensus was reached for 32 statements, and four items were ultimately agreed upon SMBG after round 2. There was a high degree of consensus that isCGM helps to evaluate glycemic variability, improves HbA1c levels, and can guide therapeutic changes in type 1 diabetes patients. However, there was no consensus on the routine use of the interquartile range to evaluate glycemic variability or the selection of HbA1c as the main parameter for monitoring glycemic control. CONCLUSIONS: Most Spanish experts believe that the isCGM system is appropriate for: (1) identifying glycemic variability and facilitating its management, (2) evaluating hyperglycemia as a complement of HbA1c levels, and (3) guiding therapeutic decisions on insulin selection and dosing. The isCGM system is a useful tool for patients and health care professionals to improve glycemic control in insulin-dependent diabetes.

Connected Insulin Pens and Caps: An Expert's Recommendation from the Area of Diabetes of the Spanish Endocrinology and Nutrition Society (SEEN).

Undoubtedly, technological advances have revolutionised diabetes management in recent years. The development of advanced closed hybrid loop insulin pumps or continuous glucose monitoring (CGM) systems, among others, have increased the quality of life and improved glycaemic control of people with diabetes. However, only some patients have access to such technology, and only some want to use it. CGM has become much more widespread, but in terms of insulin delivery, most people with type 1 diabetes (T1D) and almost all people with type 2 diabetes (T2D) on insulin therapy are treated with multiple-dose insulin injections (MDI) rather than an insulin pump. For these patients, using connected insulin pens or caps has shown benefits in reducing missed insulin injections and promoting correct administration over time. In addition, using these devices improves the quality of life and user satisfaction. The integration of insulin injection and CGM data facilitates both users and the healthcare team to analyse glucose control and implement appropriate therapeutic changes, reducing therapeutic inertia. This expert's recommendation reviews the characteristics of the devices marketed or in the process of being marketed and their available scientific evidence. Finally, it suggests the profile of users and professionals who would benefit most, the barriers to its generalisation and the changes in the care model that implementing these devices can bring with it.

Gestational weight gain and pregnancy outcomes in women with type 1 and type 2 diabetes mellitus.

AIMS: We aimed to explore the relationship between gestational weight gain (GWG) after Institute of Medicine (IOM) and pregnancy outcomes in women with type 1 and type 2 diabetes. METHODS: Retrospective cohort study at a tertiary medical center (1981-2011). OUTCOME VARIABLES: 2 maternal and 14 fetal. Main exposure variable: GWG according to IOM. We calculated crude and adjusted ORs as well as population attributable (PAF) and preventable fractions (PPF) for significant positive and negative associations, respectively. RESULTS: We evaluated 633 pregnant women with type 1 or type 2 diabetes. GWG was insufficient (iGWG) in 16.7% and excessive (eGWG) in 50.7%. In the adjusted analysis, GWG according to IOM was significantly associated with maternal outcomes (pregnancy-induced hypertension and cesarean delivery) and four fetal outcomes (large-for-gestational age, macrosomia, small-for-gestational age and neonatal respiratory distress). The association with large-for-gestational age newborns was negative for iGWG (0.48, CI 95% 0.25-0.94) and positive for eGWG (1.76, CI 95% 1.18-2.63). In addition, iGWG was associated with a higher risk of small-for-gestational age newborns and respiratory distress and eGWG with a higher risk of pregnancy-induced hypertension, caesarean delivery and macrosomia. PAF and PPF ranged from the 20.4% PPF of iGWG for large-for-gestational age to 56.5% PAF of eGWG for macrosomia. CONCLUSION: In this cohort of women with type 1 or type 2 diabetes, inadequate GWG after IOM was associated with adverse pregnancy outcomes; associations were unfavorable for eGWG and mixed for iGWG. The attributable fractions were not moderate, pointing to the potential impact of modifying inadequate GWG.

Evaluation of the usefulness of and satisfaction with the flash glucose monitoring system (FreeStyle Libre®) guide for use in patients with type 1 diabetes⋆.

The Flash Guide (FG) for insulin dosing (A. Chico, C. González) was the first document intended for FreeStyle Libre® (FSL) user patients to help with decision-making depending on glucose level and trend. The objective of the study was to evaluate the usefulness of and the level of satisfaction with the recommendations given by the FG in a group of patients with type 1 diabetes (DM1) who were FSL users. It included 31 subjects (54% women; age 41 ± 15 years; DM duration 21 ± 14 years; 22 with FSL > 12 months) who were provided with the FG. They completed a questionnaire on decision-making depending on glucose trend in different situations (before and three months after using the FG), and a satisfaction questionnaire (ad hoc). Demographic, clinical and glycaemic control data were collected. The percentage of subjects who used glucose trend in decision-making after receiving the FG increased: for adjusting insulin (51 vs. 83; p = 0.016), action without insulin (51 vs. 90%; p = 0.001), and in special circumstances. The FG was evaluated as very useful (4.19/5). There were no significant changes in glycaemic control, although the percentage of data gathered increased significantly (89.07 vs. 94.46%; p = 0.042). In conclusion, the FG was evaluated well for managing glucose trends with FSL by the patients with DM1 analysed, increasing their use of trend in decision-making, with no changes in glycaemic control, but with more data gathered.

Continuous Subcutaneous Insulin Infusion in Type 1 Diabetes Mellitus Patients: Results from the Spanish National Registry.

Aim: To analyze the clinical effect of continuous subcutaneous insulin infusion (CSII) in type 1 diabetes mellitus (T1D) patients in the Spanish real-world scenario. Methods: All T1D patients on CSII registered in the SPAnish Insulin Pump (SPAIP) registry were included. The primary efficacy outcome was change in HbA1c during follow-up. Secondary efficacy outcomes included: insulin pump indications, diabetes complication rates, insulin and pump use, and continuous glucose monitoring (CGM) glycometrics. Patient data were typed through the web-based SPAIP registry. Results: Data from 2979 T1D patients treated with CSII were analyzed. The median age was 44 years (interquartile range [IQR] 34-52 years), and T1D duration was 27 years (IQR 18-35 years). The median duration of CSII therapy was 6 years (IQR 3-10 years). The main indications for treatment were suboptimal glycemic control (33.8%), hypoglycemia (22.1%), and increased glycemic variability (18.8%). Glycated hemoglobin decreased by 6 mmol/mol (95% CI, -5 to -6 mmol/mol, P < 0.001) [-0.5%, 95% CI, -0.4 to -0.5, P < 0.001] during the follow-up. The percentage of patients with severe hypoglycemia decreased from 14.9% to 0.9% (P < 0.001). We observed an inverse correlation between final HbA1c levels and CGM adherence (R = -0.24, P < 0.001) or percentage of time with active hybrid closed-loop functions (R = -0.25, P < 0.001). Conclusions: CSII treatment was associated with a sustained improvement in glycemic control in the Spanish population. This benefit was greater among patients with higher CGM or active hybrid closed-loop functions adherence. The protocol was publicly registered at ClinicalTrials.gov (NCT04761094).

Defective involuntary attention to novelty in type 1 diabetes and impaired awareness of hypoglycaemia.

AIM: To determine if there are differences in terms of neurophysiology and neurocognitive functioning in a group of type 1 diabetes (T1D) patients regarding hypoglycaemia awareness. METHODS: 27 patients with T1D were classified according to Clarke score as having impaired awareness of hypoglycaemia (IAH; n = 11) or normal awareness to hypoglycaemia (NAH; n = 16). We measured several clinical and sociodemographic variables and cognitive performance using neuropsychological tests. Electroencephalography was assessed during an auditory oddball task. We compared the groups in terms of clinical/sociodemographic variables as well as two event-related brain potentials (ERPs): The P3a which is associated with automatic orientation of attention to novelty, and the P3b which is associated with target detection and processing. RESULTS: The IAH group performed significantly worse on the Trail Making Test part A (TMT-A) (p = 0.05). Compared to the NAH group, P3a and P3b amplitudes in the frontal-central sites were significantly lower in the IAH group (p < 0.05). The P3a was strongly associated with worse performance on the TMT-A in the IAH group (r = 0.540; p < 0.005) CONCLUSION: IAH is accompanied by decreased neurophysiological activity in ERPs associated with information processing and with the automatic orientation of attention to novelty and environmental changes. These findings suggest a possible framework to better understand the cognitive origin of IAH in this patient population.