Diabetic Ketoacidosis at Onset of Type 1 Diabetes and Glycemic Outcomes with Closed-Loop Insulin Delivery.

The presence of diabetic ketoacidosis (DKA) at diagnosis of type 1 diabetes (T1D) is associated with higher glycated hemoglobin levels over time. We evaluated whether hybrid-closed loop (HCL) therapy from onset of T1D could prevent the adverse impact of DKA at diagnosis on long-term glycemic outcomes. This was a posthoc analysis from 51 adolescents using HCL from diagnosis of T1D as part of the CLOuD trial (NCT02871089). We compared glycemic and insulin metrics between adolescents with (n = 17) and without (n = 34) DKA at diagnosis. Participants with and without DKA at diagnosis had similar time in target glucose range 3.9-10.0 mmol/L (70-180 mg/dL), time below range (<3.9 mmol/L, <70 mg/dL) and HbA1c at 6, 12, and 24 months. While insulin requirements at 6 months were higher in those with DKA at diagnosis, this was not statistically significant after adjusting for bodyweight. Residual C-peptide secretion was similar between groups. We conclude that HCL therapy may mitigate against the negative glycemic effects of DKA at T1D diagnosis.

B-Clear Phase 2b Study Design: Establishing the Efficacy and Safety of Bepirovirsen in Patients with Chronic Hepatitis B Virus Infection.

INTRODUCTION: Bepirovirsen (GSK3228836) is an antisense oligonucleotide that induced rapid and prolonged hepatitis B surface antigen (HBsAg) reduction with a favorable safety profile following 4 weeks of treatment in participants with chronic hepatitis B virus (HBV) infection. The objective of the phase 2b study B-Clear is to access the efficacy and safety of bepirovirsen in participants with chronic HBV infection. METHODS: B-Clear is a phase 2b, multicenter, randomized, partial-blind (sponsor/participant-blinded, investigator-unblinded) study in participants with chronic HBV infection receiving stable nucleos(t)ide analogue (On-NA) or not currently receiving NA therapy (Not-on-NA). Eligibility criteria included HBsAg > 100 IU/mL, HBV DNA < 90 IU/mL (On-NA) or > 2000 IU/mL (Not-on-NA), and alanine aminotransferase ≤ 2 × upper limit of normal (ULN; On-NA) or < 3 × ULN (Not-on-NA). Participants were randomized 3:3:3:1 to one of four treatment arms, with treatment administered weekly as subcutaneous injections with or without loading doses (LD) on days 4 and 11: bepirovirsen 300 mg (with 300 mg LD) for 24 weeks; bepirovirsen 300 mg (with 300 mg LD) for 12 weeks then bepirovirsen 150 mg for 12 weeks; bepirovirsen 300 mg (with 300 mg LD) for 12 weeks then placebo for 12 weeks; placebo for 12 weeks (with placebo LD) then bepirovirsen 300 mg without LD for 12 weeks. PLANNED OUTCOMES: The primary endpoint of the study was HBsAg < lower limit of detection and HBV DNA < lower limit of quantification for 24 weeks after the end of bepirovirsen treatment in the absence of rescue medication. The study enrolled 457 participants (On-NA, n = 227; Not-on-NA, n = 230) and the last patient visit occurred in March 2022. The novel design of the B-Clear study will allow assessment of HBsAg and HBV DNA seroclearance post bepirovirsen treatment discontinuation in the presence and absence of background NA therapy. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov (NCT04449029; GSK study 209668).

Time Spent in Hypoglycemia According to Age and Time of Day: Observations During Closed-Loop Insulin Delivery.

Objective: We aimed to assess whether percentage of time spent in hypoglycemia during closed-loop insulin delivery differs by age group and time of day. Methods: We retrospectively analyzed data from hybrid closed-loop studies involving young children (2-7 years), children and adolescents (8-18 years), adults (19-59 years), and older adults (≥60 years) with type 1 diabetes. Main outcome was time spent in hypoglycemia <3.9 mmol/L (<70 mg/dL). Eight weeks of data for 88 participants were analyzed. Results: Median time spent in hypoglycemia over the 24-h period was highest in children and adolescents (4.4% [interquartile range 2.4-5.0]) and very young children (4.0% [3.4-5.2]), followed by adults (2.7% [1.7-4.0]), and older adults (1.8% [1.2-2.2]); P < 0.001 for difference between age groups. Time spent in hypoglycemia during nighttime (midnight-05:59) was lower than during daytime (06:00-23:59) across all age groups. Conclusion: Time in hypoglycemia was highest in the pediatric age group during closed-loop insulin delivery. Hypoglycemia burden was lowest overnight across all age groups.

Safety of User-Initiated Intensification of Insulin Delivery Using Cambridge Hybrid Closed-Loop Algorithm.

OBJECTIVE: Many hybrid closed-loop (HCL) systems struggle to manage unusually high glucose levels as experienced with intercurrent illness or pre-menstrually. Manual correction boluses may be needed, increasing hypoglycemia risk with overcorrection. The Cambridge HCL system includes a user-initiated algorithm intensification mode ("Boost"), activation of which increases automated insulin delivery by approximately 35%, while remaining glucose-responsive. In this analysis, we assessed the safety of "Boost" mode. METHODS: We retrospectively analyzed data from closed-loop studies involving young children (1-7 years, n = 24), children and adolescents (10-17 years, n = 19), adults (≥24 years, n = 13), and older adults (≥60 years, n = 20) with type 1 diabetes. Outcomes were calculated per participant for days with ≥30 minutes of "Boost" use versus days with no "Boost" use. Participants with <10 "Boost" days were excluded. The main outcome was time spent in hypoglycemia <70 and <54 mg/dL. RESULTS: Eight weeks of data for 76 participants were analyzed. There was no difference in time spent <70 and <54 mg/dL between "Boost" days and "non-Boost" days; mean difference: -0.10% (95% confidence interval [CI] -0.28 to 0.07; P = .249) time <70 mg/dL, and 0.03 (-0.04 to 0.09; P = .416) time < 54 mg/dL. Time in significant hyperglycemia >300 mg/dL was 1.39 percentage points (1.01 to 1.77; P < .001) higher on "Boost" days, with higher mean glucose and lower time in target range (P < .001). CONCLUSIONS: Use of an algorithm intensification mode in HCL therapy is safe across all age groups with type 1 diabetes. The higher time in hyperglycemia observed on "Boost" days suggests that users are more likely to use algorithm intensification on days with extreme hyperglycemic excursions.

Evaluating the Impact of Applying Personal Glucose Targets in a Closed-Loop System for People With Type 1 Diabetes.

BACKGROUND: CamAPS FX is a hybrid closed-loop smartphone app used to manage type one diabetes. The closed-loop algorithm has a default target glucose of 5.8 mmol/L (104.5 mg/dL), but users can select personal glucose targets (adjustable between 4.4 mmol/L and 11.0 mmol/L [79 mg/dL and 198 mg/dL, respectively]). METHOD: In this post-hoc analysis, we evaluated the impact of personal glucose targets on glycemic control using data from participants in five randomized controlled trials. RESULTS: Personal glucose targets were widely used, with 20.3% of all days in the data set having a target outside the default target bin (5.5-6.0 mmol/L [99-108 mg/dL]). Personal glucose targets >6.5 mmol/L (117 mg/dL) were associated with significantly less time in target range (3.9-10.0 mmol/L [70-180 mg/dL]; 6.5-7.0 mmol/L [117-126 mg/dL]: mean difference = -3.2 percentage points [95% CI: -5.3 to -1.2; P < .001]; 7.0-7.5 mmol/L [126-135 mg/dL]: -10.8 percentage points [95% CI: -14.1 to -7.6; P < .001]). Personal targets >6.5 mmol/L (117 mg/dL) were associated with significantly lower time (<3.9 mmol/L [<70 mg/dL]; 6.5-7.0 mmol/L [117-126 mg/dL]: -1.85 percentage points [95% CI: -2.37 to -1.34; P < .001]; 7.0-7.5 mmol/L [126-135 mg/dL]: -2.68 percentage points [95% CI: -3.49 to -1.86; P < .001]). CONCLUSIONS: Discrete study populations showed differences in glucose control when applying similar personal targets.

Cambridge Hybrid Closed-Loop System in Very Young Children With Type 1 Diabetes Reduces Caregivers' Fear of Hypoglycemia and Improves Their Well-Being.

OBJECTIVE: To evaluate the impact of CamAPS FX hybrid closed-loop (HCL) automated insulin delivery in very young children with type 1 diabetes (T1D) on caregivers' well-being, fear of hypoglycemia, and sleepiness. RESEARCH DESIGN AND METHODS: We conducted a multinational, open-label, randomized crossover study. Children (age 1-7 years) with T1D received treatment for two 4-month periods in random order, comparing HCL with sensor augmented pump (control). At baseline and after each treatment period, caregivers were invited to complete World Health Organization-Five Well-Being Index, Hypoglycemia Fear Survey, and Epworth Sleepiness Scale questionnaires. RESULTS: Caregivers of 74 children (mean ± SD age 5 ± 2 years and baseline HbA1c 7.3 ± 0.7%; 42% female) participated. Results revealed significantly lower scores for hypoglycemia fear (P < 0.001) and higher scores for well-being (P < 0.001) after HCL treatment. A trend toward a reduction in sleepiness score was observed (P = 0.09). CONCLUSIONS: Our results suggest better well-being and less hypoglycemia fear in caregivers of very young children with T1D on CamAPS FX HCL.

Closed-Loop Therapy and Preservation of C-Peptide Secretion in Type 1 Diabetes.

BACKGROUND: Whether improved glucose control with hybrid closed-loop therapy can preserve C-peptide secretion as compared with standard insulin therapy in persons with new-onset type 1 diabetes is unclear. METHODS: In a multicenter, open-label, parallel-group, randomized trial, we assigned youths 10.0 to 16.9 years of age within 21 days after a diagnosis of type 1 diabetes to receive hybrid closed-loop therapy or standard insulin therapy (control) for 24 months. The primary end point was the area under the curve (AUC) for the plasma C-peptide level (after a mixed-meal tolerance test) at 12 months after diagnosis. The analysis was performed on an intention-to-treat basis. RESULTS: A total of 97 participants (mean [±SD] age, 12±2 years) underwent randomization: 51 were assigned to receive closed-loop therapy and 46 to receive control therapy. The AUC for the C-peptide level at 12 months (primary end point) did not differ significantly between the two groups (geometric mean, 0.35 pmol per milliliter [interquartile range, 0.16 to 0.49] with closed-loop therapy and 0.46 pmol per milliliter [interquartile range, 0.22 to 0.69] with control therapy; mean adjusted difference, -0.06 pmol per milliliter [95% confidence interval {CI}, -0.14 to 0.03]). There was not a substantial between-group difference in the AUC for the C-peptide level at 24 months (geometric mean, 0.18 pmol per milliliter [interquartile range, 0.06 to 0.22] with closed-loop therapy and 0.24 pmol per milliliter [interquartile range, 0.05 to 0.30] with control therapy; mean adjusted difference, -0.04 pmol per milliliter [95% CI, -0.14 to 0.06]). The arithmetic mean glycated hemoglobin level was lower in the closed-loop group than in the control group by 4 mmol per mole (0.4 percentage points; 95% CI, 0 to 8 mmol per mole [0.0 to 0.7 percentage points]) at 12 months and by 11 mmol per mole (1.0 percentage points; 95% CI, 7 to 15 mmol per mole [0.5 to 1.5 percentage points]) at 24 months. Five cases of severe hypoglycemia occurred in the closed-loop group (in 3 participants), and one occurred in the control group; one case of diabetic ketoacidosis occurred in the closed-loop group. CONCLUSIONS: In youths with new-onset type 1 diabetes, intensive glucose control for 24 months did not appear to prevent the decline in residual C-peptide secretion. (Funded by the National Institute for Health and Care Research and others; CLOuD ClinicalTrials.gov number, NCT02871089.).

Phase IIa, randomised, double-blind study of GSK3389404 in patients with chronic hepatitis B on stable nucleos(t)ide therapy.

BACKGROUND & AIMS: Bepirovirsen, an antisense oligonucleotide targeting pregenomic and mRNA transcripts of HBV, has been conjugated to N-acetyl galactosamine (GSK3389404) to enhance hepatocyte delivery. This dose-finding study was the first to assess GSK3389404 for chronic HBV infection. METHODS: This phase IIa, randomised, double-blind, placebo-controlled, 2-part study was conducted in 22 centres in Asia (NCT03020745). Pharmacokinetic findings from Part 1 informed Part 2 dosing. In Part 2, patients with chronic hepatitis B on nucleos(t)ide analogue therapy were randomised 11:2 to GSK3389404 (30, 60, 120 mg weekly or 120 mg bi-weekly) or placebo until Day 85. Coprimary endpoints included HBsAg response (≥1.5 log10 IU/ml reduction from baseline) rate, safety and pharmacokinetics. RESULTS: Parts 1 and 2 included 12 (9 GSK3389404, 3 placebo) and 66 patients (56 GSK3389404, 10 placebo), respectively. In Part 2, one patient each in the 60 mg weekly, 120 mg weekly and 120 mg bi-weekly arms achieved a HBsAg response. HBsAg reductions were dose-dependent (Day 85: mean 0.34 [60 mg weekly] to 0.75 log10 IU/ml [120 mg weekly]) and occurred in hepatitis B e antigen-positive and -negative patients. No patient achieved HBsAg seroclearance. 43/56 (77%) GSK3389404- and 9/10 (90%) placebo-treated patients reported adverse events. No deaths were reported. Alanine aminotransferase flares (>2x upper limit of normal) occurred in 2 GSK3389404-treated patients (120 mg weekly, 120 mg bi-weekly); both were associated with decreased HBsAg, but neither was considered a responder. GSK3389404 plasma concentrations peaked 2-4 hours post dose; mean plasma half-life was 3-5 hours. CONCLUSIONS: GSK3389404 showed an acceptable safety profile and target engagement, with dose-dependent reductions in HBsAg. However, no efficacious dosing regimen was identified. CLINICAL TRIAL NUMBER: NCT03020745. LAY SUMMARY: Hepatitis B virus (HBV) can result in chronic HBV infection, which may ultimately lead to chronic liver disease, primary liver cancer and death; HBV proteins may prevent the immune system from successfully controlling the virus. GSK3389404 is an investigational agent that targets HBV RNA, resulting in reduced viral protein production. This study assessed the safety of GSK3389404 and its ability to reduce the viral proteins in patients with chronic HBV infection. GSK3389404 showed dose-dependent reduction in hepatitis B surface antigen, with an acceptable safety profile. While no clear optimal dose was identified, the findings from this study may help in the development of improved treatment options for patients with chronic HBV infections.

Selenium Supplementation in Pregnancy-Maternal and Newborn Outcomes.

Background: Several studies have suggested that increased oxidative stress during pregnancy may be associated with adverse maternal and foetal outcomes. As selenium is an essential mineral with an antioxidant role, our aim was to perform a systematic review of the existing literature reporting the effects of selenium supplementation during pregnancy on maternal and neonatal outcomes. Materials and Methods: Six electronic databases (Medline, Embase, Cochrane Library, Web of Science, Scopus, and PubMed) were searched for studies reporting the effects of selenium supplementation during pregnancy and the postpartum period on maternal and neonatal outcomes. Only randomised controlled trials on human subjects reported in English and published up to October 2021 were included. Quality assessments were conducted using the modified Downs and Black quality assessment tool. Data were extracted using a narrative synthesis. Results: Twenty-two articles were included in our systematic review (seventeen reported on maternal outcomes, two on newborn outcomes, and three on both). Maternal studies reported the effects of selenium supplementation in the prevention of thyroid dysfunction, gestational diabetes, pregnancy-induced hypertension/preeclampsia, oxidative stress, postpartum depression, premature rupture of membranes, intrauterine growth retardation, breastmilk composition, and HIV-positive women. Newborn studies reported the effects of maternal selenium supplementation on foetal oxidation stress, foetal lipid profile, neonatal hyperbilirubinemia, and newborn outcomes in HIV-positive mothers. The majority of studies were inappropriately designed to establish clinical or scientific utility. Of interest, four studies reported that selenium supplementation reduced the incidence of thyroid dysfunction and permanent hypothyroidism during the postpartum period by reducing thyroid peroxidase and thyroglobulin antibody titres. Conclusion: The evidence supporting selenium supplementation during pregnancy is poor and there is a need for appropriately designed randomised controlled trials before routine use can be recommended.

Cambridge hybrid closed-loop algorithm in children and adolescents with type 1 diabetes: a multicentre 6-month randomised controlled trial.

BACKGROUND: Closed-loop insulin delivery systems have the potential to address suboptimal glucose control in children and adolescents with type 1 diabetes. We compared safety and efficacy of the Cambridge hybrid closed-loop algorithm with usual care over 6 months in this population. METHODS: In a multicentre, multinational, parallel randomised controlled trial, participants aged 6-18 years using insulin pump therapy were recruited at seven UK and five US paediatric diabetes centres. Key inclusion criteria were diagnosis of type 1 diabetes for at least 12 months, insulin pump therapy for at least 3 months, and screening HbA1c levels between 53 and 86 mmol/mol (7·0-10·0%). Using block randomisation and central randomisation software, we randomly assigned participants to either closed-loop insulin delivery (closed-loop group) or to usual care with insulin pump therapy (control group) for 6 months. Randomisation was stratified at each centre by local baseline HbA1c. The Cambridge closed-loop algorithm running on a smartphone was used with either (1) a modified Medtronic 640G pump, Medtronic Guardian 3 sensor, and Medtronic prototype phone enclosure (FlorenceM configuration), or (2) a Sooil Dana RS pump and Dexcom G6 sensor (CamAPS FX configuration). The primary endpoint was change in HbA1c at 6 months combining data from both configurations. The primary analysis was done in all randomised patients (intention to treat). Trial registration ClinicalTrials.gov, NCT02925299. FINDINGS: Of 147 people initially screened, 133 participants (mean age 13·0 years [SD 2·8]; 57% female, 43% male) were randomly assigned to either the closed-loop group (n=65) or the control group (n=68). Mean baseline HbA1c was 8·2% (SD 0·7) in the closed-loop group and 8·3% (0·7) in the control group. At 6 months, HbA1c was lower in the closed-loop group than in the control group (between-group difference -3·5 mmol/mol (95% CI -6·5 to -0·5 [-0·32 percentage points, -0·59 to -0·04]; p=0·023). Closed-loop usage was low with FlorenceM due to failing phone enclosures (median 40% [IQR 26-53]), but consistently high with CamAPS FX (93% [88-96]), impacting efficacy. A total of 155 adverse events occurred after randomisation (67 in the closed-loop group, 88 in the control group), including seven severe hypoglycaemia events (four in the closed-loop group, three in the control group), two diabetic ketoacidosis events (both in the closed-loop group), and two non-treatment-related serious adverse events. There were 23 reportable hyperglycaemia events (11 in the closed-loop group, 12 in the control group), which did not meet criteria for diabetic ketoacidosis. INTERPRETATION: The Cambridge hybrid closed-loop algorithm had an acceptable safety profile, and improved glycaemic control in children and adolescents with type 1 diabetes. To ensure optimal efficacy of the closed-loop system, usage needs to be consistently high, as demonstrated with CamAPS FX. FUNDING: National Institute of Diabetes and Digestive and Kidney Diseases.

Randomized Trial of Closed-Loop Control in Very Young Children with Type 1 Diabetes.

BACKGROUND: The possible advantage of hybrid closed-loop therapy (i.e., artificial pancreas) over sensor-augmented pump therapy in very young children with type 1 diabetes is unclear. METHODS: In this multicenter, randomized, crossover trial, we recruited children 1 to 7 years of age with type 1 diabetes who were receiving insulin-pump therapy at seven centers across Austria, Germany, Luxembourg, and the United Kingdom. Participants received treatment in two 16-week periods, in random order, in which the closed-loop system was compared with sensor-augmented pump therapy (control). The primary end point was the between-treatment difference in the percentage of time that the sensor glucose measurement was in the target range (70 to 180 mg per deciliter) during each 16-week period. The analysis was conducted according to the intention-to-treat principle. Key secondary end points included the percentage of time spent in a hyperglycemic state (glucose level, >180 mg per deciliter), the glycated hemoglobin level, the mean sensor glucose level, and the percentage of time spent in a hypoglycemic state (glucose level, <70 mg per deciliter). Safety was assessed. RESULTS: A total of 74 participants underwent randomization. The mean (±SD) age of the participants was 5.6±1.6 years, and the baseline glycated hemoglobin level was 7.3±0.7%. The percentage of time with the glucose level in the target range was 8.7 percentage points (95% confidence interval [CI], 7.4 to 9.9) higher during the closed-loop period than during the control period (P<0.001). The mean adjusted difference (closed-loop minus control) in the percentage of time spent in a hyperglycemic state was -8.5 percentage points (95% CI, -9.9 to -7.1), the difference in the glycated hemoglobin level was -0.4 percentage points (95% CI, -0.5 to -0.3), and the difference in the mean sensor glucose level was -12.3 mg per deciliter (95% CI, -14.8 to -9.8) (P<0.001 for all comparisons). The time spent in a hypoglycemic state was similar with the two treatments (P = 0.74). The median time spent in the closed-loop mode was 95% (interquartile range, 92 to 97) over the 16-week closed-loop period. One serious adverse event of severe hypoglycemia occurred during the closed-loop period. One serious adverse event that was deemed to be unrelated to treatment occurred. CONCLUSIONS: A hybrid closed-loop system significantly improved glycemic control in very young children with type 1 diabetes, without increasing the time spent in hypoglycemia. (Funded by the European Commission and others; ClinicalTrials.gov number, NCT03784027.).

The Role of Dietary Advanced Glycation End Products in Metabolic Dysfunction.

Advanced glycation end products (AGEs) are a heterogeneous group of molecules produced, non-enzymatically, from the interaction between reducing sugars and the free amino groups of proteins, nucleic acids, and lipids. AGEs are formed as a normal consequence of metabolism but can also be absorbed from the diet. They have been widely implicated in the complications of diabetes affecting cardiovascular health, the nervous system, eyes, and kidneys. Increased levels of AGEs are also detrimental to metabolic health and may contribute to the metabolic abnormalities induced by the Western diet, which is high in processed foods and represents a significant source of AGEs. While increased AGE levels are a consequence of diabetic hyperglycaemia, AGEs themselves activate signaling pathways, which compromise insulin signaling and pancreatic ß-cell function, thus, contributing to the development of type 2 diabetes mellitus (T2DM). Furthermore, AGEs may also contribute to the obesogenic effects of the Western diet by promoting hypothalamic inflammation and disrupting the central control of energy balance. Here, the role of dietary AGEs in metabolic dysfunction is reviewed with a focus on the mechanisms underpinning their detrimental role in insulin resistance, pancreatic ß-cell dysfunction, hypothalamic control of energy balance, and the pathogenesis of T2DM and obesity.

Early and reversible changes to the hippocampal proteome in mice on a high-fat diet.

BACKGROUND: The rise in global obesity makes it crucial to understand how diet drives obesity-related health conditions, such as premature cognitive decline and Alzheimer's disease (AD). In AD hippocampal-dependent episodic memory is one of the first types of memory to be impaired. Previous studies have shown that in mice fed a high-fat diet (HFD) episodic memory is rapidly but reversibly impaired. METHODS: In this study we use hippocampal proteomics to investigate the effects of HFD in the hippocampus. Mice were fed either a low-fat diet (LFD) or HFD containing either 10% or 60% (Kcal) from fat for 3 days, 1 week or 2 weeks. One group of mice were fed the HFD for 1 week and then returned to the LFD for a further week. Primary hippocampal cultures were challenged with palmitic acid (PA), the most common long-chain saturated FA in the Western diet, and with the anti-inflammatory, n-3 polyunsaturated FA, docosahexaenoic acid (DHA), or a combination of the two to ascertain effects of these fatty acids on dendritic structure. RESULTS: HFD-induced changes occur in hippocampal proteins involved in metabolism, inflammation, cell stress, cell signalling, and the cytoskeleton after 3 days, 1 week and 2 weeks of HFD. Replacement of the HFD after 1 week by a low-fat diet (LFD) for a further week resulted in partial recovery of the hippocampal proteome. Microtubule-associated protein 2 (MAP2), one of the earliest proteins changed, was used to investigate the impact of fatty acids (FAs) on hippocampal neuronal morphology. PA challenge resulted in shorter and less arborised dendrites while DHA had no effect when applied alone but counteracted the effects of PA when FAs were used in combination. Dendritic morphology recovered when PA was removed from the cell culture media. CONCLUSION: This study provides evidence for the rapid and reversible effects of diet on the hippocampal proteome and the impact of PA and DHA on dendritic structure.

A high-fat diet induces rapid changes in the mouse hypothalamic proteome.

BACKGROUND: Prolonged over-consumption of a high-fat diet (HFD) commonly leads to obesity and insulin resistance. However, even 3 days of HFD consumption has been linked to inflammation within the key homeostatic brain region, the hypothalamus. METHODS: Mice were fed either a low-fat diet (LFD) or HFD containing 10% or 60% (Kcal) respectively from fat for 3 days. Mice were weighed, food intake measured and glucose tolerance calculated using intraperitoneal glucose tolerance tests (IPGTT). Proteomic analysis was carried out to determine if hypothalamic proteins were changed by a HFD. The direct effects of dietary fatty acids on mitochondrial morphology and on one of the proteins most changed by a HFD, dihydropyrimidinase-related protein 2 (DRP-2) a microtubule-associated protein which regulates microtubule dynamics, were also tested in mHypoE-N42 (N42) neuronal cells challenged with palmitic acid (PA) and oleic acid (OA). RESULTS: Mice on the HFD, as expected, showed increased adiposity and glucose intolerance. Hypothalamic proteomic analysis revealed changes in 104 spots after 3 days on HFD, which, when identified by LC/MS/MS, were found to represent 78 proteins mainly associated with cytoskeleton and synaptic plasticity, stress response, glucose metabolism and mitochondrial function. Over half of the changed proteins have also been reported to be changed in neurodegenerative conditions such as Alzheimer's disease. Also,in N42 neurons mitochondrial morphology and DRP-2 levels were altered by PA but not by OA. CONCLUSION: These results demonstrate that within 3 days, there is a relatively large effect of HFD on the hypothalamic proteome indicative of cellular stress, altered synaptic plasticity and mitochondrial function, but not inflammation. Changes in N42 cells show an effect of PA but not OA on DRP-2 and on mitochondrial morphology indicating that long-chain saturated fatty acids damage neuronal function.

Participants' Experiences of, and Views About, Daytime Use of a Day-and-Night Hybrid Closed-Loop System in Real Life Settings: Longitudinal Qualitative Study.

OBJECTIVE: To explore individuals' experiences of daytime use of a day-and-night hybrid closed-loop system, their information and support needs, and their views about how future systems could be improved. RESEARCH DESIGN AND METHODS: Twenty-four adults, adolescents, and parents were interviewed before using a hybrid day-and-night closed-loop system and 3 months later, data were analyzed thematically. RESULTS: Participants praised the closed loop's ability to respond to high and low blood glucose in ways which extended beyond their own capabilities and to act as a safety net and mop up errors, such as when a mealtime bolus was forgotten or unplanned activity was undertaken. Participants also described feeling less burdened by diabetes as a consequence and more able to lead flexible, spontaneous lives. Contrary to their initial expectations, and after trust in the system had been established, most individuals wanted opportunities to collaborate with the closed loop to optimize its effectiveness. Such individuals expressed a need to communicate information, such as when routines changed or to indicate different intensities of physical activity. While individuals valued frequent contact with staff in the initial month of use, most felt that their long-term support needs would be no greater than when using an insulin pump. CONCLUSIONS: While participants reported substantial benefits to using the closed loop during the day, they also identified ways in which the technology could be refined and education and training tailored to optimize effective use. Our findings suggest that mainstreaming this technology will not necessarily lead to increased demands on clinical staff.

SerpinA3N is a novel hypothalamic gene upregulated by a high-fat diet and leptin in mice.

BACKGROUND: Energy homeostasis is regulated by the hypothalamus but fails when animals are fed a high-fat diet (HFD), and leptin insensitivity and obesity develops. To elucidate the possible mechanisms underlying these effects, a microarray-based transcriptomics approach was used to identify novel genes regulated by HFD and leptin in the mouse hypothalamus. RESULTS: Mouse global array data identified serpinA3N as a novel gene highly upregulated by both a HFD and leptin challenge. In situ hybridisation showed serpinA3N expression upregulation by HFD and leptin in all major hypothalamic nuclei in agreement with transcriptomic gene expression data. Immunohistochemistry and studies in the hypothalamic clonal neuronal cell line, mHypoE-N42 (N42), confirmed that alpha 1-antichymotrypsin (α1AC), the protein encoded by serpinA3, is localised to neurons and revealed that it is secreted into the media. SerpinA3N expression in N42 neurons is upregulated by palmitic acid and by leptin, together with IL-6 and TNFα, and all three genes are downregulated by the anti-inflammatory monounsaturated fat, oleic acid. Additionally, palmitate upregulation of serpinA3 in N42 neurons is blocked by the NFκB inhibitor, BAY11, and the upregulation of serpinA3N expression in the hypothalamus by HFD is blunted in IL-1 receptor 1 knockout (IL-1R1 -/- ) mice. CONCLUSIONS: These data demonstrate that serpinA3 expression is implicated in nutritionally mediated hypothalamic inflammation.

Rapid and reversible impairment of episodic memory by a high-fat diet in mice.

Alzheimer's disease is a leading cause of morbidity and mortality with no cure and only limited treatment available. Obesity and type 2 diabetes are positively associated with the development of premature cognitive decline and Alzheimer's disease, linking diet with these conditions. Here we demonstrate that in mice episodic memory, together with spatial and contextual associative memory, is compromised after only one day of high-fat diet. However, object memory remains intact. This shows not only a more rapid effect than previously reported but also that more complex memories are at higher risk of being compromised by a high-fat diet. In addition, we show that these memory deficits are rapidly reversed by switching mice from a high-fat diet back to a low-fat diet. These findings have important implications for the contribution of nutrition to the development of cognitive decline and Alzheimer's disease.

Outcomes of using flash glucose monitoring technology by children and young people with type 1 diabetes in a single arm study.

BACKGROUND AND OBJECTIVE: Outcomes of using flash glucose monitoring have been reported in adults. This trial evaluated use in children and teenagers with type 1 diabetes. METHODS: Prospective, single arm, non-inferiority multicenter study to demonstrate equivalence of time in range (TIR [70-180 mg/dL]) by comparing 14-day masked sensor wear (baseline) with self-monitored blood glucose (SMBG) testing to the final 14-days of 8-week open-label system use for diabetes self-management including insulin dosing. RESULTS: A total of 76 children and teenagers (46.1% male; age 10.3 ± 4.0 years, type 1 diabetes duration 5.4 ± 3.7 years; mean ± SD) from 10 sites participated. TIR improved significantly by 0.9 ± 2.8 h/d (P = 0.005) vs SMBG baseline. Time in hyperglycemia (>180 mg/dL) reduced by -1.2 ± 3.3 h/d (P = 0.004). HbA1c reduced by -0.4% (-4.4 mmol/mol), from 7.9 ± 1.0% (62.9 ± 11.2 mmol/mol) baseline to 7.5 ± 0.9% (58.5 ± 9.8 mmol/mol) study end (P < 0.0001) with reductions across all age-subgroups (4-6, 7-12 and 13-17 years). Time in hypoglycemia (<70 mg/dL) was unaffected. Throughout the treatment phase system utilization was 91% ± 9; sensor scanning was 12.9 ± 5.7/d with SMBG dropping to 1.6 ± 1.9 from 7.7 ± 2.5/d. Diabetes Treatment Satisfaction Questionnaire "Total Treatment Satisfaction" score improved for parents (P < 0.0001) and teenagers (P < 0.0001). No adverse events (n = 121) were associated with sensor accuracy, 42 participants experienced sensor insertion signs and symptoms. Three participants experienced three mild device-related (sensor wear) symptoms, resolving quickly (without treatment [n = 2], non-prescription antihistamines [n = 1]). CONCLUSIONS: Children with diabetes improved glycemic control safely and effectively with short-term flash glucose monitoring compared to use of SMBG in a single arm study.