Bihormonal fully closed-loop system for the treatment of type 1 diabetes: a real-world multicentre, prospective, single-arm trial in the Netherlands.

BACKGROUND: Management of insulin administration for intake of carbohydrates and physical activity can be burdensome for people with type 1 diabetes on hybrid closed-loop systems. Bihormonal fully closed-loop (FCL) systems could help reduce this burden. In this trial, we assessed the long-term performance and safety of a bihormonal FCL system. METHODS: The FCL system (Inreda AP; Inreda Diabetic, Goor, Netherlands) that uses two hormones (insulin and glucagon) was assessed in a 1 year, multicentre, prospective, single-arm intervention trial in adults with type 1 diabetes. Participants were recruited in eight outpatient clinics in the Netherlands. We included adults with type 1 diabetes aged 18-75 years who had been using flash glucose monitoring or continuous glucose monitors for at least 3 months. Study visits were integrated into standard care, usually every three months, to evaluate glycaemic control, adverse events, and person-reported outcomes. The primary endpoint was time in range (TIR; glucose concentration 3·9-10·0 mmol/L) after 1 year. The study is registered in the Dutch Trial Register, NL9578. FINDINGS: Between June 1, 2021, and March 2, 2022, we screened 90 individuals and enrolled 82 participants; 78 were included in the analyses. 79 started the intervention and 71 were included in the 12 month analysis. Mean age was 47.7 (SD 12·4) years and 38 (49%) were female participants. The mean preintervention TIR of participants was 55·5% (SD 17·2). After 1 year of FCL treatment, mean TIR was 80·3% (SD 5·4) and median time below range was 1·36% (IQR 0·80-2·11). Questionnaire scores improved on Problem Areas in Diabetes (PAID) from 30·0 (IQR 18·8-41·3) preintervention to 10·0 (IQR 3·8-21·3; p<0·0001) at 12 months and on World Health Organization-Five Well-Being Index (WHO-5) from 60·0 (IQR 44·0-72·0) preintervention to 76·0 (IQR 60·0-80·0; p<0·0001) at 12 months. Five serious adverse events were reported (one cerebellar stroke, two severe hypoglycaemic, and two hyperglycaemic events). INTERPRETATION: Real-world data obtained in this trial demonstrate that use of the bihormonal FCL system was associated with good glycaemic control in patients who completed 1 year of treatment, and could help relieve these individuals with type 1 diabetes from making treatment decisions and the burden of carbohydrate counting. FUNDING: Inreda Diabetic.

Transient thyroiditis after parathyroidectomy for tertiary hyperparathyroidism.

Thyrotoxicosis due to thyroiditis is predominantly caused by infection or autoimmune disease of the thyroid. Parathyroid surgery however, is a lesser known cause of thyroiditis, due to thyroid manipulation. We treated a patient who developed transient symptomatic thyroiditis following parathyroid surgery for tertiary hyperparathyroidism. Therefore, the differential diagnosis for patients with symptoms after parathyroid surgery should include transient thyroiditis.

Variants in Pharmacokinetic Transporters and Glycemic Response to Metformin: A Metgen Meta-Analysis.

Therapeutic response to metformin, a first-line drug for type 2 diabetes (T2D), is highly variable, in part likely due to genetic factors. To date, metformin pharmacogenetic studies have mainly focused on the impact of variants in metformin transporter genes, with inconsistent results. To clarify the significance of these variants in glycemic response to metformin in T2D, we performed a large-scale meta-analysis across the cohorts of the Metformin Genetics Consortium (MetGen). Nine candidate polymorphisms in five transporter genes (organic cation transporter [OCT]1, OCT2, multidrug and toxin extrusion transporter [MATE]1, MATE2-K, and OCTN1) were analyzed in up to 7,968 individuals. None of the variants showed a significant effect on metformin response in the primary analysis, or in the exploratory secondary analyses, when patients were stratified according to possible confounding genotypes or prescribed a daily dose of metformin. Our results suggest that candidate transporter gene variants have little contribution to variability in glycemic response to metformin in T2D.

Phenotypic heterogeneity in cultured skin fibroblasts from patients with disorders of peroxisome biogenesis belonging to the same complementation group.

We have studied fibroblast cell lines derived from a control subject (cell line 85AD5035F) and three patients clinically described as having the Zellweger syndrome (cell line W78/515), the infantile form of Refsum disease (cell line BOV84AD) and hyperpipecolic acidaemia (cell line GM3605), respectively. The mutant cell lines belonged to the same complementation group. The fibroblasts were cultured under identical conditions and were harvested at different time intervals after reaching confluence. Several peroxisomal parameters were determined. In agreement with previous reports, a lowered enzymic activity of acyl-CoA: dihydroxyacetonephosphate acyltransferase and a decrease in latent catalase clearly distinguished the patient cell lines from the control cell line. However, the cell lines exhibited a phenotypic heterogeneity. This was most strikingly encountered when cells were processed for indirect immunofluorescence microscopy and stained with anti-(catalase). The control cells exhibited a punctate fluorescence, which is indicative of the presence of catalase in peroxisomes. In the mutant cell line W78/515 a diffuse fluorescence was observed, indicative of the presence of catalase in the cytosol. In the other two mutant cell lines a punctate fluorescence was observed in some of the cells. Moreover, clear differences in the extent of proteolytic processing of acyl-CoA oxidase were detected. The mutant cell line BOV84AD displayed a control-like pattern with all molecular forms of acyl-CoA oxidase (72, 52 and 20 kDa) present, whereas in the W78/515 cell line only the 72 kDa component could be visualised. The GM3605 cell line was intermediate in this respect.

Bioactivation of selenocysteine Se-conjugates by a highly purified rat renal cysteine conjugate beta-lyase/glutamine transaminase K.

Selenocysteine Se-conjugates have recently been proposed as potential prodrugs to target pharmacologically active selenol compounds to the kidney. Although rat renal cytosol displayed a high activity of beta-elimination activity toward these substrates, the enzymes involved in this activation pathway as yet have not been identified. In the present study, the possible involvement of cysteine conjugate beta-lyase/glutamine transaminase K (beta-lyase/GTK) in cytosolic activity was investigated. To this end, the enzyme kinetics of 15 differentially substituted selenocysteine Se-conjugates and 11 cysteine S-conjugates was determined using highly purified rat renal beta-lyase/GTK. The results demonstrate that most selenocysteine Se-conjugates are beta-eliminated at a very high activity by purified beta-lyase/GTK, implicating an important role of this protein in the previously reported beta-elimination reactions in rat renal cytosol. As indicated by the rapid consumption of alpha-keto-gamma-methiolbutyric acid, purified beta-lyase/GTK also catalyzed transamination reactions, which appeared to even exceed that of beta-elimination. The corresponding sulfur analogs also showed significant transamination but were beta-eliminated at an extremely low rate. Comparison of the obtained enzyme kinetic data of purified beta-lyase/GTK with previously obtained data from rat renal cytosol showed a poor correlation. By determining the activity profiles of cytosolic fractions applied to anion exchange fast protein liquid chromatography and gel filtration chromatography, the involvement of multiple enzymes in the beta-elimination of selenocysteine Se-conjugates in rat renal cytosol was demonstrated. The identity and characteristics of these alternative selenocysteine conjugate beta-lyases, however, remain to be established.

Clogging of biliary endoprostheses: a new perspective.

Endoscopic palliation with biliary endoprostheses is now an established treatment for benign and malignant strictures of the biliary tree. These endoprostheses, however, tend to clog with time. We investigated this problem by undertaking in vitro studies on stents of different designs made of different polymer materials. The stent that performed best was then tested in an in vivo trial. There was a direct relation in vitro between the frictional coefficient of a polymer and the amount of encrusted material. Catheters perfused in bacterially contaminated bile, irrespective of material and design, accrued significantly more sludge than catheters perfused with sterilised bile. The presence of side holes significantly increased the amount of sludge in the stents, but eliminated any differences between the various materials. We therefore investigated the effect of omitting side holes in a clinical trial which consisted of two groups of 20 patients each. The group treated with conventional stents accrued significantly more sludge in the stents than the group treated with experimental stents without side holes (p less than 0.05). The absence of side holes did not cause incomplete drainage or increase morbidity. Side holes are detrimental to stent patency, which is adversely affected by other factors including bacteria and proteins.

A placebo-controlled study on the efficacy of aspirin and doxycycline in preventing clogging of biliary endoprostheses.

Sixty patients in whom a biliary endoprosthesis was inserted were randomized to receive: (1) placebo, (2) aspirin, or (3) doxycycline, to study the effect on the process of sludge formation. After 2 months all endoprostheses were changed, and the amount and composition of the sludge in the patent stents was analyzed. Half of the patients dropped out. The major component (56%) of the sludge of all groups was protein. No insoluble residue was present. Major deposits of sludge were found at irregularities in the stent wall (side flaps). Both doxycycline and aspirin reduced the dry weight of the sludge. Doxycycline significantly reduced the amount of protein, but scanning electron microscopy still showed abundant bacterial growth. Aspirin reduced the content of all sludge components including protein, suggesting that it decreases "stickiness" of bile. Surprisingly, doxycycline significantly decreased the death rate in the 2 months of the study. We present further evidence for a primary role of protein deposition in the early stages of stent occlusion. This process can be partly inhibited by doxycycline and probably also by aspirin, which could lead to a significant increase in stent patency.