The type 2 diabetes gene product STARD10 is a phosphoinositide-binding protein that controls insulin secretory granule biogenesis.

OBJECTIVE: Risk alleles for type 2 diabetes at the STARD10 locus are associated with lowered STARD10 expression in the ß-cell, impaired glucose-induced insulin secretion, and decreased circulating proinsulin:insulin ratios. Although likely to serve as a mediator of intracellular lipid transfer, the identity of the transported lipids and thus the pathways through which STARD10 regulates ß-cell function are not understood. The aim of this study was to identify the lipids transported and affected by STARD10 in the ß-cell and the role of the protein in controlling proinsulin processing and insulin granule biogenesis and maturation. METHODS: We used isolated islets from mice deleted selectively in the ß-cell for Stard10 (ßStard10KO) and performed electron microscopy, pulse-chase, RNA sequencing, and lipidomic analyses. Proteomic analysis of STARD10 binding partners was executed in the INS1 (832/13) cell line. X-ray crystallography followed by molecular docking and lipid overlay assay was performed on purified STARD10 protein. RESULTS: ßStard10KO islets had a sharply altered dense core granule appearance, with a dramatic increase in the number of "rod-like" dense cores. Correspondingly, basal secretion of proinsulin was increased versus wild-type islets. The solution of the crystal structure of STARD10 to 2.3 Å resolution revealed a binding pocket capable of accommodating polyphosphoinositides, and STARD10 was shown to bind to inositides phosphorylated at the 3' position. Lipidomic analysis of ßStard10KO islets demonstrated changes in phosphatidylinositol levels, and the inositol lipid kinase PIP4K2C was identified as a STARD10 binding partner. Also consistent with roles for STARD10 in phosphoinositide signalling, the phosphoinositide-binding proteins Pirt and Synaptotagmin 1 were amongst the differentially expressed genes in ßStard10KO islets. CONCLUSION: Our data indicate that STARD10 binds to, and may transport, phosphatidylinositides, influencing membrane lipid composition, insulin granule biosynthesis, and insulin processing.

Depressive Symptoms, Co-Morbidities, and Glycemic Control in Hong Kong Chinese Elderly Patients With Type 2 Diabetes Mellitus.

BACKGROUND AND OBJECTIVES: Undiagnosed depression is an important comorbidity in type 2 diabetes (T2D) which can be detected using the Geriatric Depression Scale (GDS-15) questionnaire. In this cross-sectional study, we examined the associations of depression using GDS score with control of cardiometabolic risk factors and health status in elderly patients with T2D. SETTING AND PARTICIPANTS: Between February and December 2013, patients aged ≥65 years who underwent structured comprehensive assessment as a quality improvement program at the Diabetes Center of a teaching hospital were invited to complete the GDS-15 questionnaire. MAIN OUTCOME MEASURES: Depression was defined as a GDS score ≥7. Demographic data, prior history of co-morbidities, frequency of self-reported hypoglycemia, and attainment of treatment targets defined as HbA1c, <7%, blood pressure <130/80 mmHg, and LDL-C <2.6 mmol/L were documented. RESULTS: Among 325 participants (65% male, median [interquartile range] age: 69 [8] years), 42 (13%) had depression. Patients with depression had longer disease durations (mean ± SD: 15.1 ± 9.1 vs. 11.6 ± 8.1 years, P = 0.02), more frequent self-reported hypoglycemic events (17 vs. 6%, P = 0.03) and were less likely to attain all three treatment targets (0 vs. 16%, P = 0.004) than those without depression. On multivariable analysis, patients with depression had an odds ratio of 2.84 (95% confidence intervals: 1.35-6.00, P = 0.006) of reporting prior history of co-morbidities. CONCLUSION: In elderly patients with T2D, depression was not uncommon especially in those with poor control of risk factors, hypoglycemia, and co-morbidities. Inclusion of GDS-15 questionnaire during structured assessment for complications and risk factors can identify these high-risk patients for more holistic management of their physical and mental health.

The Longitudinal Effects of Persistent Apnea on Cerebral Oxygenation in Infants Born Preterm.

OBJECTIVE: To assess the incidence and impact of persistent apnea on heart rate (HR), oxygen saturation (SpO2), and brain tissue oxygenation index (TOI) over the first 6 months after term equivalent age in ex-preterm infants. STUDY DESIGN: Twenty-four preterm infants born between 27 and 36 weeks of gestational age were studied with daytime polysomnography at 2-4 weeks, 2-3 months, and 5-6 months post-term corrected age. Apneas lasting ≥3 seconds were included and maximal percentage changes (nadir) in HR, SpO2, and tissue oxygenation index (TOI, NIRO-200 Hamamatsu) from baseline were analyzed. RESULTS: A total of 253 apneas were recorded at 2-4 weeks, 203 at 2-3 months, and 148 at 5-6 months. There was no effect of gestational age at birth, sleep state, or sleep position on apnea duration, nadir HR, SpO2, or TOI. At 2-4 weeks, the nadirs in HR (-11.1 ± 1.2 bpm) and TOI (-4.4 ± 1.0%) were significantly less than at 2-3 months (HR: -13.5 ± 1.2 bpm, P < .05; TOI: -7.5 ± 1.1 %, P < .05) and at 5-6 months (HR: -13.2 ± 1.3 bpm, P < .01; TOI: -9.3 ± 1.2%, P < .01). CONCLUSIONS: In ex-preterm infants, apneas were frequent and associated with decreases in heart rate and cerebral oxygenation, which were more marked at 2-3 months and 5-6 months than at 2-4 weeks. Although events were short, they may contribute to the adverse neurocognitive outcomes that are common in ex-preterm children.

MARCH1 regulates insulin sensitivity by controlling cell surface insulin receptor levels.

Insulin resistance is a key driver of type 2 diabetes (T2D) and is characterized by defective insulin receptor (INSR) signalling. Although surface INSR downregulation is a well-established contributor to insulin resistance, the underlying molecular mechanisms remain obscure. Here we show that the E3 ubiquitin ligase MARCH1 impairs cellular insulin action by degrading cell surface INSR. Using a large-scale RNA interference screen, we identify MARCH1 as a negative regulator of INSR signalling. March1 loss-of-function enhances, and March1 overexpression impairs, hepatic insulin sensitivity in mice. MARCH1 ubiquitinates INSR to decrease cell surface INSR levels, but unlike other INSR ubiquitin ligases, MARCH1 acts in the basal state rather than after insulin stimulation. Thus, MARCH1 may help set the basal gain of insulin signalling. MARCH1 expression is increased in white adipose tissue of obese humans, suggesting that MARCH1 contributes to the pathophysiology of T2D and could be a new therapeutic target.

Acute renal failure associated with Legionella pneumonia and acute cholecystitis.

BACKGROUND AND AIMS: Acute cholecystitis in critically ill patients has a high morbidity and mortality. We observed a number of patients presenting with Legionella pneumonia and acute renal failure who subsequently developed acute cholecystitis. There has previously been no reported association between Legionella pneumonia, renal failure and cholecystitis, prompting this examination of the cases and review of the available literature. METHODS: The Western Hospital patient record discharge codes (DRG) from 1993 to 2001 were searched retrospectively for all cases of Legionella pneumonia or acute renal failure requiring dialysis (ARF) at presentation or during their period of hospitalization. Acute cholecystitis was then included as a cross-search and results analysed. RESULTS: Twenty-six cases of isolated Legionella pneumonia and 112 of ARF were identified with a further 10 having both conditions simultaneously. Of these 10 cases, three were identified as also having acute cholecystitis. The combination of Legionella pneumonia and ARF was associated with an increased risk of acute cholecystitis (P = 0.002) whereas neither condition in isolation demonstrated this association. CONCLUSIONS: Patients with Legionella pneumonia can become critically ill with multiple complications including acute renal failure requiring dialysis. In this setting, they may have an increased risk of developing acute cholecystitis, which clinically can be difficult to ascertain. Diagnosis requires a high index of suspicion and vigilance.

Surface modification of TiO2 by a ruthenium(II) polypyridyl complex via silyl-linkage for the sensitized photocatalytic degradation of carbon tetrachloride by visible irradiation.

A new ruthenium(II) photosensitizer, [Ru(II)(py-pzH)(3)](2+) (where py-pzH=3-(2'-pyridyl)pyrazole), has been synthesized. The complex displayed outstanding excited state redox properties (estimated Ru(III)/Ru(II)* approximately -1.24 V vs. NHE) and was expected to sensitize the injection of electrons into the conduction band of anatase TiO(2) upon visible irradiation. The photosensitizer was anchored onto the surface of anatase TiO(2) particles via in situ silylation. The silyl-linkage displayed excellent stability in both aqueous media, over a wide pH range, and in common organic solvents. The resultant material, TiO(2)-[Ru(II)(py-pz-Si identical with )(3)], was found to be able to mediate degradation of CCl(4) in neutral aqueous medium under broad band visible irradiation (lambda>450 nm). The relation between the rate of degradation and concentration of substrate was explored and the mechanism of the photodegradation of the perhalogenated organic was discussed.