The medial nucleus of the trapezoid body (MNTB) is specialized for high frequency firing by expression of Kv3 channels, which minimize action potential (AP) duration, and Kv1 channels, which suppress multiple AP firing, during each calyceal giant EPSC. However, the outward K(+) current in MNTB neurons is dominated by another unidentified delayed rectifier. It has slow kinetics and a peak conductance of approximately 37 nS; it is half-activated at -9.2 +/- 2.1 mV and half-inactivated at -35.9 +/- 1.5 mV. It is blocked by several non-specific potassium channel antagonists including quinine (100 microm) and high concentrations of extracellular tetraethylammonium (TEA; IC(50) = 11.8 mM), but no specific antagonists were found. These characteristics are similar to recombinant Kv2-mediated currents. Quantitative RT-PCR showed that Kv2.2 mRNA was much more prevalent than Kv2.1 in the MNTB. A Kv2.2 antibody showed specific staining and Western blots confirmed that it recognized a protein approximately 110 kDa which was absent in brainstem tissue from a Kv2.2 knockout mouse. Confocal imaging showed that Kv2.2 was highly expressed in axon initial segments of MNTB neurons. In the absence of a specific antagonist, Hodgkin-Huxley modelling of voltage-gated conductances showed that Kv2.2 has a minor role during single APs (due to its slow activation) but assists recovery of voltage-gated sodium channels (Nav) from inactivation by hyperpolarizing interspike potentials during repetitive AP firing. Current-clamp recordings during high frequency firing and characterization of Nav inactivation confirmed this hypothesis. We conclude that Kv2.2-containing channels have a distinctive initial segment location and crucial function in maintaining AP amplitude by regulating the interspike potential during high frequency firing.
To evaluate the user-reported usefulness and effectiveness of the first structured education module for children with Type 1 Diabetes Mellitus (T1DM) in Wales – SEREN 'Diabetes at Diagnosis'.
Methods
This reports the qualitative findings from a national retrospective questionnaire-based service evaluation. The SEREN programme is the first standardised Diabetes structured education programme for children and young people (CYP) and their families in Wales. The first module, 'Diabetes at Diagnosis', delivers education to empower CYP and their families with self-management of T1DM after diagnosis. It was introduced across Wales in 2016-17. 12/14 paediatric diabetes centres in Wales took part in the evaluation. A national diabetes register was used to select the pre-SEREN cohort of children diagnosed with T1DM one year before the introduction of the module and the post-SEREN cohort were diagnosed one year after its introduction. Primary outcomes were CYP and parent reported user-friendliness and effectiveness. Data from free text questionnaire responses were subjected to a thematic analysis. The evaluation also included clinical outcomes (Quality of life using PedsQL scoring, HbA1c at six and 12 months, service engagement and diabetes-related hospital admissions in the first year) which have been reported separately.1
Results
89/106 responded pre-SEREN and 108/115 post-SEREN, with no demographic differences in age, sex, ethnicity, deprivation quintile and HbA1c at diagnosis. Of these, 45 CYP and their families pre-SEREN, and 93 post-SEREN provided free text feedback on what they felt was useful in the education they received and what could be improved. SEREN resources were frequently described as 'practical', 'easy to understand' and 'helped with self-management'. Suggestions for improvement included provision of more emotional and psychological support, further sessions, information on long term impact and help to engage with other families already living with T1DM. Quantitative results from the service evaluation are published elsewhere.1
Conclusion
This reports qualitative findings of a national service evaluation of the only standardised T1DM structured education programme in use for CYP and their families throughout Wales. These findings have helped inform and improve the revision of the first module, 'Diabetes at Diagnosis'. Further evaluation from the cohort who have now received subsequent SEREN modules and health care professionals that deliver the programme is required to evaluate the full impact of the SEREN programme. With the rising incidence of T1DM, it is important that health systems invest in improving health responsiveness and patient empowerment for CYP and families living with this life-long condition.
Reference
D'Souza RS, Ryan M, Hawkes E, et al. Questionnaire-based service evaluation of the efficacy and usefulness of SEREN: a structured education programme for children and young people diagnosed with type 1 diabetes mellitus. BMJ Open Quality 2021;10:e001337. doi:10.1136/bmjoq-2021-001337
Type 2 diabetes is common and is a leading cause of morbidity and disability.
Objective
To review the evidence on screening for prediabetes and diabetes to inform the US Preventive Services Task Force (USPSTF).
Data Sources
PubMed/MEDLINE, Cochrane Library, and trial registries through September 2019; references; and experts; literature surveillance through May 21, 2021.
Study Selection
English-language controlled studies evaluating screening or interventions for prediabetes or diabetes that was screen detected or recently diagnosed.
Data Extraction and Synthesis
Dual review of abstracts, full-text articles, and study quality; qualitative synthesis of findings; meta-analyses conducted when at least 3 similar studies were available.
Main Outcomes and Measures
Mortality, cardiovascular morbidity, diabetes-related morbidity, development of diabetes, quality of life, and harms.
Results
The review included 89 publications (N = 68 882). Two randomized clinical trials (RCTs) (25 120 participants) found no significant difference between screening and control groups for all-cause or cause-specific mortality at 10 years. For harms (eg, anxiety or worry), the trials reported no significant differences between screening and control groups. For recently diagnosed (not screen-detected) diabetes, 5 RCTs (5138 participants) were included. In the UK Prospective Diabetes Study, health outcomes were improved with intensive glucose control with sulfonylureas or insulin. For example, for all-cause mortality the relative risk (RR) was 0.87 (95% CI, 0.79 to 0.96) over 20 years (10-year posttrial assessment). For overweight persons, intensive glucose control with metformin improved health outcomes at the 10-year follow-up (eg, all-cause mortality: RR, 0.64 [95% CI, 0.45 to 0.91]), and benefits were maintained longer term. Lifestyle interventions (most involving >360 minutes) for obese or overweight persons with prediabetes were associated with reductions in the incidence of diabetes (23 RCTs; pooled RR, 0.78 [95% CI, 0.69 to 0.88]). Lifestyle interventions were also associated with improved intermediate outcomes, such as reduced weight, body mass index, systolic blood pressure, and diastolic blood pressure (pooled weighted mean difference, −1.7 mm Hg [95% CI, −2.6 to −0.8] and −1.2 mm Hg [95% CI, −2.0 to −0.4], respectively). Metformin was associated with a significant reduction in diabetes incidence (pooled RR, 0.73 [95% CI, 0.64 to 0.83]) and reduction in weight and body mass index.
Conclusions and Relevance
Trials of screening for diabetes found no significant mortality benefit but had insufficient data to assess other health outcomes; evidence on harms of screening was limited. For persons with recently diagnosed (not screen-detected) diabetes, interventions improved health outcomes; for obese or overweight persons with prediabetes, interventions were associated with reduced incidence of diabetes and improvement in other intermediate outcomes.
To assess the dose-related effects of sotagliflozin, a novel dual inhibitor of sodium-glucose co-transporters-1 and -2, in type 1 diabetes (T1D).In this 12-week, multicentre, randomized, double-blind, placebo-controlled dose-ranging trial, adults with T1D were randomized to once-daily placebo (n = 36) or sotagliflozin 75 mg (n = 35), 200 mg (n = 35) or 400 mg (n = 35). Insulin was maintained at baseline doses. The primary endpoint was least squares mean (LSM) change in glycated haemoglobin (HbA1c) from baseline. Other endpoints included proportion of participants with ≥0.5% HbA1c reduction and assessments of 2-hour postprandial glucose (PPG), weight, and urinary glucose excretion (UGE).From a mean baseline of 8.0% ± 0.8% (full study population), placebo-adjusted LSM HbA1c decreased by 0.3% (P = .07), 0.5% (P < .001) and 0.4% (P = .006) with sotagliflozin 75 mg, 200 mg and 400 mg, respectively, at week 12. In the placebo and sotagliflozin 75 mg, 200 mg and 400 mg groups, 33.3%, 37.1%, 80.0% and 65.7% of participants achieved an HbA1c reduction ≥0.5%. Placebo-adjusted PPG decreased by 22.2 mg/dL (P = .28), 28.7 mg/dL (P = .16) and 50.2 mg/dL (P = .013), UGE increased by 41.8 g/d (P = .006), 57.7 g/d (P < .001) and 70.5 g/d (P < .001), and weight decreased by 1.3 kg (P = .038), 2.4 kg (P < .001) and 2.6 kg (P < .001) with sotagliflozin 75 mg, 200 mg and 400 mg, respectively. One case of severe hypoglycaemia occurred in each sotagliflozin group and one case of diabetic ketoacidosis (DKA) occurred with sotagliflozin 400 mg.Combined with stable insulin doses, sotagliflozin 200 mg and 400 mg improved glycaemic control and weight in adults with T1D. Sotagliflozin 400 mg reduced PPG levels. UGE increased with all sotagliflozin doses. Rates of severe hypoglycaemia and DKA were low (NCT02459899).
