Reducing Diabetes Burden in Medtronic's Automated Insulin Delivery Systems.

Background: The MiniMed™ 780G advanced hybrid closed-loop system (MM780G) builds on the basal automation and low-glucose protection features of the MiniMed™ 670G and 770G systems. While previous publications have focused on glycemic control improvements with MM780G, burden reduction has not been fully described. Methods: Data from two 3-month pivotal trials for the MM670G with Guardian™ Sensor 3 (GS3) (104 adults; 125 children) and MM780G with Guardian™ 4 Sensor (G4S) (67 adults;109 children) were compared. Real-world data (RWD) from United States users (N = 3851) transitioning from MM770G+GS3 to MM780G+G4S were also analyzed. Analyses included a new metric for diabetes management burden (i.e., pentagon composite metric), glycemic outcomes and system burden (e.g., closed-loop exits and fingersticks per day). Results: Diabetes burden metric (-22.8% and -28.5%), time in range (+3.1% [*P = 0.035] and +6.4% [P < 0.001]) and time below range (-1.8% [*P < 0.001] and -0.7% [*P < 0.001]) significantly improved, compared to MM670G for adult and pediatric participants, respectively. The pediatric mean sensor glucose (SG) reduced by -8.6 mg/dL (*P < 0.001), while the adults' saw no change. Closed-loop use significantly increased for both cohorts (+17.1% [*P < 0.001] and +20.5% [*P < 0.001]). Closed-loop exits were significantly reduced to about 1 per week (-0.5 [*P < 0.001] and -0.7 [*P < 0.001]); fingerstick tests were also reduced (-6.2 [*P < 0.001] and -6.9 [*P < 0.001]). Similar outcomes were observed from U.S. RWD. Conclusions: MiniMed™ 780G with G4S use was associated with significant reduction in diabetes management burden with fewer closed-loop exits, fingersticks and other interactions, and improvements in glycemic control when compared to the MiniMed™ 670G with GS3.

Systematic Review and Meta-Analysis of the Effect of Osteoporosis on Fusion Rates and Complications Following Surgery for Degenerative Cervical Spine Pathology.

BACKGROUND: As the elderly population grows, the increasing prevalence of osteoporosis presents a unique challenge for surgeons. Decreased bone strength and quality are associated with hardware failure and impaired bone healing, which may increase the rate of revision surgery and the development of complications. The purpose of this review is to determine the impact of osteoporosis on postoperative outcomes for patients with cervical degenerative disease or deformity. METHODS: A systematic review using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and Medical Subject Headings terms involving spine surgery for cervical degenerative disease and osteoporosis were performed. This review focused on radiographic outcomes, as well as surgical and medical complications. RESULTS: There were 16 studies included in the degenerative group and 9 in the deformity group. Across degenerative studies, lower bone mineral density was associated with increased rates of cage subsidence in osteoporotic patients undergoing operative treatment for cervical degenerative disease. Most studies reported varied results on the relationship between osteoporosis and other outcomes such as revision and readmission rates, costs, and perioperative complications. Our meta-analysis suggests that osteoporotic patients carry a greater risk of reduced fusion rates at 6 months and 1 year postoperatively. With respect to cervical deformity correction, although individual complication rates were unchanged with osteoporosis, the collective risk of incurring any complication may be increased in patients with poor bone stock. CONCLUSIONS: Overall, the literature suggests that outcomes for osteoporotic patients after cervical spine surgery are multifactorial. Osteoporosis seems to be a significant risk factor for developing cage subsidence and pseudarthrosis postoperatively, whereas reports on medical and hospital-related metrics were inconclusive. Our findings highlight the challenges of caring for osteoporotic patients and underline the need for adequately powered studies to understand how osteoporosis changes the risk index of patients undergoing cervical spine surgery. CLINICAL RELEVANCE: In patients undergoing cervical spine surgery for degenerative disease, osteoporosis is a significant risk factor for long-term postoperative complications-notably cage subsidence and pseudarthrosis. Given the elective nature of these procedures, interdisciplinary collaboration between providers should be routinely implemented to enable medical optimization of patients prior to cervical spine surgery.

Determinants of the Cancer Drug Funding Process in Canada.

Background: Canada has a publicly funded healthcare system with a complex drug funding process. After Health Canada approval to market a drug, the pan-Canadian Oncology Drug Review (pCODR) (now renamed the CADTH reimbursement review) makes a non-binding funding recommendation to the Canadian provinces (except Quebec), which each then decide whether the drug will be publicly funded. We identified the determinants of funding in this process. Methods: We analyzed drugs for advanced lung (n = 15), breast (n = 8), colorectal (CRC) (n = 7), melanoma (n = 10), and neuroendocrine (NET) (n = 3) cancers undergoing the funding decision process from 2011 to 2019. Determinants of funding assessed in the model included list price, cancer type, drug class, and pCODR recommendation. The primary outcome was the correlation between list price and time to funding (TTF: Health Canada approval to first provincial funding). Secondary outcomes included an exploratory analysis of predictors of drug funding. Results: We analyzed 43 drugs: targeted agents 72%, immunotherapy 20%, chemotherapy 7%. A total of 72% were funded in at least one province. Median TTF was 379 days (IQR 203−601). Median list price (28-day course) was CAD 8213 (IQR CAD 5391−9445). Higher list price was not correlated with TTF (correlation coefficient −0.20, p = 0.28). There was no association between list price and pCODR recommendation or the decision to fund in at least one province. A positive pCODR recommendation correlated with the provinces' funding decisions (p < 0.001), where 89% of drugs with a positive recommendation were funded and 100% of drugs with a negative recommendation were not funded. Tumor type was predictive of TTF (p < 0.001): CRC drugs were the slowest at a median of 2541 days (IQR 702−4379), and NETs were the quickest at a median of 0 days (IQR 0−502). Cancer type predicted decision to fund in at least one province (p = 0.005), with funding for 100% of NET drugs at the high end and 29% of CRC drugs at the low end. Drug class was predictive of TTF (p = 0.01): 465 days (IQR 245−702) for targeted agents, 443 days (IQR 298−587) for chemotherapy, and 339 days (IQR 164−446) for immunotherapy. Conclusions: Determinants of drug funding included cancer type, drug class, and pCODR recommendation but not list price. Factors other than cost were more heavily weighted in the funding decisions of cancer drugs in Canadian provinces.

Measurement of carotid plaque burden: A tool for predicting and preventing dementia?

Introduction: Carotid plaque burden is a strong predictor of stroke risk, and preventing stroke reduces the risk of dementia. Treating carotid plaque burden markedly reduces the risk of stroke. Methods: Among patients age 65-80 years attending a stroke prevention clinic, we identified those with a carotid plaque burden in the top 20% of Total Plaque Area (High TPA) and the bottom 20% (Low TPA) and performed cognitive tests: The Montreal Cognitive Assessment test (MoCA), the WAIS-III Digit Symbol-Coding Test (DSST) and Trail-Making Test (TMT) part A and B. Results: There were 31 patients recruited; 11 Low TPA (5 men) and 20 High TPA (17 men), p = 0.04. TPA was 35 ± 25 mm2 in the Low TPA vs.392 ± 169 mm2 in the High TPA group (0.0001). Patients with a high plaque burden had significantly worse performance on all the cognitive tests, all p< 0.05. Discussion: A high carotid plaque burden identifies patients at risk of cognitive impairment. Because carotid plaque burden is treatable, and treating it markedly reduces the risk of stroke, we suggest that measurement of plaque burden is a useful tool for both prediction of cognitive impairment, and prevention of dementia.

Spatial proteomics defines the content of trafficking vesicles captured by golgin tethers.

Intracellular traffic between compartments of the secretory and endocytic pathways is mediated by vesicle-based carriers. The proteomes of carriers destined for many organelles are ill-defined because the vesicular intermediates are transient, low-abundance and difficult to purify. Here, we combine vesicle relocalisation with organelle proteomics and Bayesian analysis to define the content of different endosome-derived vesicles destined for the trans-Golgi network (TGN). The golgin coiled-coil proteins golgin-97 and GCC88, shown previously to capture endosome-derived vesicles at the TGN, were individually relocalised to mitochondria and the content of the subsequently re-routed vesicles was determined by organelle proteomics. Our findings reveal 45 integral and 51 peripheral membrane proteins re-routed by golgin-97, evidence for a distinct class of vesicles shared by golgin-97 and GCC88, and various cargoes specific to individual golgins. These results illustrate a general strategy for analysing intracellular sub-proteomes by combining acute cellular re-wiring with high-resolution spatial proteomics.

Inverse Association between Serotonin 2A Receptor Antagonist Medication Use and Mortality in Severe COVID-19 Infection.

Advanced age and medical co-morbidity are strong predictors of mortality in COVID-19 infection. Yet few studies (to date) have specifically addressed risk factors associated with COVID-19 mortality in a high-risk subgroup of older US adults having one or more chronic diseases. Our hypothesis is that medications having 'off-target' anti-inflammatory effects may play a role in modulating the immune response in COVID-19 infection. We analyzed baseline risk factors associated with respiratory failure or death in 55 older adult US military veterans hospitalized for COVID-19 infection during (March-June 2020) the peak of the pandemic in New Jersey. Fifty-three percent (29/55) of patients experienced respiratory failure and thirty-one percent (17/55) died. In adjusted logistic regression analysis, baseline neutrophil to lymphocyte ratio (NLR) (P=0.0035) and body mass index (P=0.03) were significant predictors of the risk for respiratory failure. Age (P=0.05) and non-use (vs. use) of psychotropic medications having serotonin 2A receptor antagonist properties (odds ratio 5.06; 95% confidence intervals 1.18-21.7; P= 0.029) was each a significant predictor of an increased risk of death. There was a significant interaction effect of age and non-use (vs.. use) of psychotropic serotonin 2A receptor antagonist medications on the odds ratio (OR) for death (P=0.011). In selected, ventilator-dependent COVID-19 pneumonia patients treated with psychotropic serotonin 2A receptor antagonist medications to control agitation and ICU delirium, there was an apparent positive association between medication use and significant rise in the absolute lymphocyte count and decrease in the neutrophil: lymphocyte ratio. Taken together, these data are the first to suggest that certain psychotropic medications used in the treatment of chronic psychiatric illness and/or for acute delirium are inversely associated with mortality in severe COVID-19 infection by unknown mechanism which may involve (in part) immunomodulatory effects.

Associations between cognitive and brain volume changes in cognitively normal older adults.

Investigation of relationships between age-related changes in regional brain volumes and changes in domain-specific cognition could provide insights into the neural underpinnings of individual differences in cognitive aging. Domain-specific cognition (memory, verbal fluency, visuospatial ability) and tests of executive function and attention (Trail-Making Test Part A and B) and 47 brain volumes of interest (VOIs) were assessed in 836 Baltimore Longitudinal Study of Aging participants with mean follow-up of 4.1 years (maximum 23.1 years). To examine the correlation between changes in domain-specific cognition and changes in brain volumes, we used bivariate linear mixed effects models with unstructured variance-covariance structure to estimate longitudinal trajectories for each variable of interest and correlations among the random effects of these measures. Higher annual rates of memory decline were associated with greater volume loss in 14 VOIs primarily within the temporal and occipital lobes. Verbal fluency decline was associated with greater ventricular enlargement and volume loss in 24 VOIs within the frontal, temporal, and parietal lobes. Decline in visuospatial ability was associated with volume loss in 3 temporal and parietal VOIs. Declines on the attentional test were associated with volume loss in 4 VOIs located within temporal and parietal lobes. Greater declines on the executive function test were associated with greater ventricular enlargement and volume loss in 10 frontal, parietal, and temporal VOIs. Our findings highlight domain-specific patterns of regional brain atrophy that may contribute to individual differences in cognitive aging.

pH Biosensing by PI4P Regulates Cargo Sorting at the TGN.

Phosphoinositides, diacylglycerolpyrophosphate, ceramide-1-phosphate, and phosphatidic acid belong to a unique class of membrane signaling lipids that contain phosphomonoesters in their headgroups having pKa values in the physiological range. The phosphomonoester headgroup of phosphatidic acid enables this lipid to act as a pH biosensor as changes in its protonation state with intracellular pH regulate binding to effector proteins. Here, we demonstrate that binding of pleckstrin homology (PH) domains to phosphatidylinositol 4-phosphate (PI4P) in the yeast trans-Golgi network (TGN) is dependent on intracellular pH, indicating PI4P is a pH biosensor. pH biosensing by TGN PI4P in response to nutrient availability governs protein sorting at the TGN, likely by regulating sterol transfer to the TGN by Osh1, a member of the conserved oxysterol-binding protein (OSBP) family of lipid transfer proteins. Thus, pH biosensing by TGN PI4P allows for direct metabolic regulation of protein trafficking and cell growth.

Potential Life-Years Lost: The Impact of the Cancer Drug Regulatory and Funding Process in Canada.

BACKGROUND: Canada has an established publicly funded health care system with a complex drug approval and funding process. After proof of efficacy (POE; key publication/presentation) and before becoming publicly accessible, each drug undergoes a Health Canada approval process, a health technology assessment (HTA), a pricing negotiation, and finally individual provincial funding agreements. We quantified potential life-years lost during this process. METHODS: We analyzed drugs for advanced lung, breast, and colorectal cancer that underwent the HTA process between 2011 and 2016. Life-years lost were calculated by multiplying documented improvement in progression-free and overall survival, number of eligible patients, and time from POE to first public funding. For conservative calculation, we assumed all eligible patients in Canada had access at the time of first public funding, whereas in reality provinces fund at different time points. RESULTS: We analyzed 21 drugs. Of these, 15 have been funded publicly. The time from POE to first public funding ranged from 14.0 to 99.2 months (median 26.6 months). Total overall life-years lost from POE to first public funding were 39,067 (lung 32,367; breast 6,691). Progression-free life-years lost from POE to first public funding were 48,037 (lung 9,139, breast 15,827, colorectal 23,071). CONCLUSION: The number of potential life-years lost during the drug regulatory and funding process in Canada is substantial, largely driven by delays to funding of colorectal cancer drugs. Recognizing that interprovincial differences exist and that eligible patients may not all receive a given drug, if even a fraction does so, the impact of delays remains substantive. Collaborative national initiatives are required to address this major barrier to treatment access. IMPLICATIONS FOR PRACTICE: Patients may spend lengthy periods of time awaiting access to new and effective cancer drugs. Patients with private drug insurance or personal funds or who reside in certain Canadian provinces may obtain some drugs sooner than others, potentially creating a two-tiered access system. The cancer drug access and public funding system must be expedited to improve equity.

Endothelial Cell Growth Promoting Activity in Graves' Disease Sera is Neutralized by Anti-Basic Fibroblast Growth Factor Antibodies in Patients with Fat Expansive but Not Infiltrative Orbitopathy.

PURPOSE: To report a case of orbital fat expansion leading to globe prolapse in a Graves' disease patient undergoing high-dose glucocorticoid therapy. To evaluate the growth factor receptor specificities of plasma autoantibodies in Graves' disease patients who exhibited contrasting subtypes of thyroid-associated ophthalmopathy, i.e. orbital fat expansion-type vs. infiltrative. METHODS: Sera from Graves' orbitopathy and control patients with or without Graves' disease were subjected to protein-A affinity chromatography to obtain immunoglobulin G. A (1/50th to 1/1600th) range in dilutions of the protein-A eluate fraction was incubated for four days at 37 degrees C with bovine pulmonary artery endothelial cells to test for endothelial cell inhibition or stimulation. Growth stimulatory autoantibodies were co-incubated with specific neutralizing anti-insulin like growth factor 1 receptor antibodies or anti-basic fibroblast growth factor antibodies to assess autoantibody specificity in contrasting Graves' orbitopathy subtypes. RESULTS: We observed increased mean endothelial cell growth promoting activity in the protein-A eluates of serum from eighteen patients with active Graves' disease (117 ± 28%, n = 18) compared to mean endothelial cell activity (89 ± 10%, n = 13, P = 0.003) in thirteen adults without Graves' disease. The protein-A eluate fraction in acute infiltrative-type Graves' orbitopathy contained a high titer (> 1:1000) of endothelial cell stimulatory activity which was significantly neutralized by specific monoclonal anti-human insulin-like growth factor 1 receptor antibodies. The protein-A eluate fraction in fat expansion-type Graves' orbitopathy contained endothelial cell inhibitory activity (at low titers) and stimulatory activity (at high titers), and the latter stimulatory activity was completely neutralized by specific anti-basic fibroblast growth factor antibodies. CONCLUSION: Graves' disease suffering globe prolapse secondary to marked orbital fat-expansion had coexisting plasma fibroblast growth factor-inhibitory and -stimulatory autoantibodies. The latter was completely neutralized by anti-basic fibroblast growth factor antibodies.

Author Correction: TBC1D23 is a bridging factor for endosomal vesicle capture by golgins at the trans-Golgi.

In the version of Supplementary Table 1 originally published with this Article, in the sheet relating to Fig. 3c, all values in the 'golgin-97-mito' column were 1.3 times larger than the actual values, which was due to author error when generating the Supplementary Table. These errors did not affect the graph in Fig. 3c, which was plotted with the correct values. Supplementary Table 1 has now been replaced so that it contains the correct values.

TBC1D23 is a bridging factor for endosomal vesicle capture by golgins at the trans-Golgi.

The specificity of membrane traffic involves tethers at destination organelles that selectively capture incoming transport vesicles to allow SNAREs on opposing membranes to then assemble and drive fusion. Tethers include both protein complexes and long coiled-coil proteins, although how they contribute to specificity remains unclear. The golgin coiled-coil proteins at the Golgi apparatus capture vesicles from different origins, but the vesicle-specific molecular cues that they recognize are unknown. Vesicle tethering is typically a transient process and therefore is challenging to interrogate in vivo. Thus, we have used a system in which an ectopic golgin causes vesicles to accumulate in a tethered state. By applying proximity biotinylation to the golgin-captured vesicles, we identify TBC1D23, an apparently catalytically inactive member of a family of Rab GTPase-activating proteins (GAPs), as a vesicle-golgin adaptor that is required for endosome-to-Golgi trafficking. The Rab GAP domain of TBC1D23 binds to a conserved motif at the tip of golgin-245 and golgin-97 at the trans-Golgi, while the C terminus binds to the WASH complex on endosome-derived vesicles. Thus, TBC1D23 is a specificity determinant that links the vesicle to the target membrane during endosome-to-Golgi trafficking.

Systematic identification of genes involved in metabolic acid stress resistance in yeast and their potential as cancer targets.

A hallmark of all primary and metastatic tumours is their high rate of glucose uptake and glycolysis. A consequence of the glycolytic phenotype is the accumulation of metabolic acid; hence, tumour cells experience considerable intracellular acid stress. To compensate, tumour cells upregulate acid pumps, which expel the metabolic acid into the surrounding tumour environment, resulting in alkalization of intracellular pH and acidification of the tumour microenvironment. Nevertheless, we have only a limited understanding of the consequences of altered intracellular pH on cell physiology, or of the genes and pathways that respond to metabolic acid stress. We have used yeast as a genetic model for metabolic acid stress with the rationale that the metabolic changes that occur in cancer that lead to intracellular acid stress are likely fundamental. Using a quantitative systems biology approach we identified 129 genes required for optimal growth under conditions of metabolic acid stress. We identified six highly conserved protein complexes with functions related to oxidative phosphorylation (mitochondrial respiratory chain complex III and IV), mitochondrial tRNA biosynthesis [glutamyl-tRNA(Gln) amidotransferase complex], histone methylation (Set1C-COMPASS), lysosome biogenesis (AP-3 adapter complex), and mRNA processing and P-body formation (PAN complex). We tested roles for two of these, AP-3 adapter complex and PAN deadenylase complex, in resistance to acid stress using a myeloid leukaemia-derived human cell line that we determined to be acid stress resistant. Loss of either complex inhibited growth of Hap1 cells at neutral pH and caused sensitivity to acid stress, indicating that AP-3 and PAN complexes are promising new targets in the treatment of cancer. Additionally, our data suggests that tumours may be genetically sensitized to acid stress and hence susceptible to acid stress-directed therapies, as many tumours accumulate mutations in mitochondrial respiratory chain complexes required for their proliferation.

Hypoglycemia Prevention and User Acceptance of an Insulin Pump System with Predictive Low Glucose Management.

BACKGROUND: The MiniMed 640G sensor-augmented insulin pump system (Medtronic, Inc., Northridge, CA) can automatically suspend insulin delivery in advance of predicted hypoglycemia and restart it upon recovery. The aims of this analysis were to determine the rate at which predicted hypoglycemia was avoided with this strategy, as well as to assess user acceptance of the system and its insulin management features. SUBJECTS AND METHODS: Forty subjects with type 1 diabetes used the system for 4 weeks. We retrospectively evaluated performance of the system, using downloaded pump and sensor data, and evaluated user acceptance via questionnaires. RESULTS: There were 2,322 suspend before low events (2.1 per subject-day). The mean (± SD) duration of pump suspension events was 56.4 ± 9.6 min, and the mean subsequent sensor glucose (SG) nadir was 71.8 ± 5.2 mg/dL. SG values following 1,930 (83.1%) of the predictive suspensions did not reach the preset low limit. Nadir SG values of ≤50 and ≤60 mg/dL were seen in 207 (8.9%) and 356 (15.3%) of the predictive suspensions, respectively. Blood glucose (BG) and SG values before and during the study were comparable (P > 0.05). The mean absolute relative difference between paired SG and BG values was 10.9 ± 13.8%. Subjects felt confident using the system, agreed that it helped protect them from hypoglycemia, and wished to continue using it. CONCLUSIONS: Automatic insulin pump suspension as implemented in the MiniMed 640G system can help patients avoid hypoglycemia, without significantly increasing hyperglycemia.

Hypoglycemia Reduction and Changes in Hemoglobin A1c in the ASPIRE In-Home Study.

BACKGROUND: ASPIRE In-Home randomized 247 subjects with type 1 diabetes to sensor-augmented pump therapy with or without the Threshold Suspend (TS) feature, which interrupts insulin delivery at a preset sensor glucose value. We studied the effects of TS on nocturnal hypoglycemia (NH) in relation to baseline hemoglobin A1c (A1C) and change in A1C during the study. MATERIALS AND METHODS: NH event rates and mean area under curve (AUC) of NH events were evaluated at different levels of baseline A1C (<7%, 7-8%, and >8%) and at different levels of changes in A1C (less than -0.3% [decreased], -0.3% to 0.3% [stable], and >0.3% [increased]), in the TS Group compared with the Control Group (sensor-augmented pump only). RESULTS: In the TS Group, 27.9% of the NH events were accompanied by a confirmatory blood glucose value, compared with 39.3% in the Control Group. Among subjects with baseline A1C levels of <7% or 7-8%, those in the TS Group had significantly lower NH event rates than those in the Control Group (P=0.001 and P=0.004, respectively). Among subjects with decreased or stable A1C levels, those in the TS Group had significantly lower NH event rates, and the events had lower AUCs (P≤0.001 for each). Among subjects with increased A1C levels, those in the TS Group had NH events with significantly lower AUCs (P<0.001). CONCLUSIONS: Use of the TS feature was associated with decreases in the rate and severity (as measured by AUC) of NH events in many subjects, including those with low baseline A1C levels and those whose A1C values decreased during the study period. Use of the TS feature can help protect against hypoglycemia in those wishing to intensify diabetes management to achieve target glucose levels.

The effects of lowering nighttime and breakfast glucose levels with sensor-augmented pump therapy on hemoglobin A1c levels in type 1 diabetes.

OBJECTIVE: This study determined the association of continuous glucose monitoring glucose (CGM-glucose) levels at different times of the day with improvement in glycated hemoglobin (HbA1c) levels. The potential application of these data is to focus effort to improve glucose control in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: Data were analyzed from 196 patients with type 1 diabetes who were randomized to receive sensor-augmented pump therapy in the 1-year STAR 3 trial. CGM-glucose values and HbA1c levels from baseline and after 1 year were evaluated to determine associations of improvement in CGM-glucose at different times of the day with longitudinal improvement in HbA1c. RESULTS: Improvement in HbA1c levels after 1 year was related to improvement in mean CGM-glucose levels in daytime (6 a.m.-midnight), overnight (midnight-6 a.m.), and each mealtime period (P<0.0001 for each). In multivariable analysis, only improvement in breakfast meal period was associated with improvement in HbA1c after 1 year, explaining 59% of the HbA1c improvement using the partial R(2) test. Moreover, among those patients who only improved CGM-glucose in the overnight period there was an associated improvement in breakfast meal period CGM-glucose of 26 ± 22 mg/dL (P<0.01). CONCLUSIONS: Breakfast period glucose improvement had the greatest effect on lowering HbA1c levels in patients with type 1 diabetes. Improving glucose control overnight resulted in subsequent improvement in the breakfast period. Although glucose control should be improved at all times, methods to improve overnight and post-breakfast glucose levels may be of primary importance in improving glucose control in patients with type 1 diabetes.

Putting the pH into phosphatidic acid signaling.

The lipid phosphatidic acid (PA) has important roles in cell signaling and metabolic regulation in all organisms. New evidence indicates that PA also has an unprecedented role as a pH biosensor, coupling changes in pH to intracellular signaling pathways. pH sensing is a property of the phosphomonoester headgroup of PA. A number of other potent signaling lipids also contain headgroups with phosphomonoesters, implying that pH sensing by lipids may be widespread in biology.

Arabidopsis ABCG transporters, which are required for export of diverse cuticular lipids, dimerize in different combinations.

ATP binding cassette (ABC) transporters play diverse roles, including lipid transport, in all kingdoms. ABCG subfamily transporters that are encoded as half-transporters require dimerization to form a functional ABC transporter. Different dimer combinations that may transport diverse substrates have been predicted from mutant phenotypes. In Arabidopsis thaliana, mutant analyses have shown that ABCG11/WBC11 and ABCG12/CER5 are required for lipid export from the epidermis to the protective cuticle. The objective of this study was to determine whether ABCG11 and ABCG12 interact with themselves or each other using bimolecular fluorescence complementation (BiFC) and protein traffic assays in vivo. With BiFC, ABCG11/ABCG12 heterodimers and ABCG11 homodimers were detected, while ABCG12 homodimers were not. Fluorescently tagged ABCG11 or ABCG12 was localized in the stem epidermal cells of abcg11 abcg12 double mutants. ABCG11 could traffic to the plasma membrane in the absence of ABCG12, suggesting that ABCG11 is capable of forming flexible dimer partnerships. By contrast, ABCG12 was retained in the endoplasmic reticulum in the absence of ABCG11, indicating that ABCG12 is only capable of forming a dimer with ABCG11 in epidermal cells. Emerging themes in ABCG transporter biology are that some ABCG proteins are promiscuous, having multiple partnerships, while other ABCG transporters form obligate heterodimers for specialized functions.