The importance of sexual dimorphism has been highlighted in recent years since the National Institutes of Health's mandate on considering sex as a biological variable. Although recent studies have taken strides to study both sexes side by side, investigations into the normal physiological differences between males and females are limited. In this study, we aimed to characterized sex-dependent differences in glucose metabolism and pancreatic β-cell physiology in normal conditions using C57BL/6J mice, the most common mouse strain used in metabolic studies. Here, we report that female mice have improved glucose and insulin tolerance associated with lower nonfasted blood glucose and insulin levels compared with male mice at 3 and 6 months of age. Both male and female animals show β-cell mass expansion from embryonic day 17.5 to adulthood, and no sex differences were observed at embryonic day 17.5, newborn, 1 month, or 3 months of age. However, 6-month-old males displayed increased β-cell mass in response to insulin resistance compared with littermate females. Molecularly, we uncovered sexual dimorphic alterations in the protein levels of nutrient sensing proteins O-GlcNAc transferase and mTOR, as well as differences in glucose-stimulus coupling mechanisms that may underlie the differences in sexually dimorphic β-cell physiology observed in C57BL/6J mice.

The nutrient sensor O-GlcNAc transferase (OGT) catalyzes posttranslational addition of O-GlcNAc onto target proteins, influencing signaling pathways in response to cellular nutrient levels. OGT is highly expressed in pancreatic glucagon-secreting cells (alpha-cells), which secrete glucagon in response to hypoglycemia. The objective of this study was to determine whether OGT is necessary for the regulation of alpha-cell mass and function in vivo. We utilized genetic manipulation to produce two alpha-cell specific OGT-knockout models: a constitutive glucagon-Cre (alpha OGT(KO)) and an inducible glucagon-Cre (i-alpha OGT(KO)), which effectively delete OGT in alpha-cells. Using approaches including immunoblotting, immunofluorescent imaging, and metabolic phenotyping in vivo, we provide the first insight on the role of O-GlcNAcylation in alpha-cell mass and function. alpha OGT(KO) mice demonstrated normal glucose tolerance and insulin sensitivity but displayed significantly lower glucagon levels during both fed and fasted states. alpha OGT(KO) mice exhibited significantly lower alpha-cell glucagon content and alpha-cell mass at 6 months of age. In fasting, alpha OGT(KO) mice showed impaired pyruvate stimulated gluconeogenesis in vivo and reduced glucagon secretion in vitro. i-alpha OGT(KO) mice showed similarly reduced blood glucagon levels, defective in vitro glucagon secretion, and normal alpha-cell mass. Interestingly, both alpha OGT(KO) and i-alpha OGT(KO) mice had no deficiency in maintaining blood glucose homeostasis under fed or fasting conditions, despite impairment in alpha-cell mass and function, and glucagon content. In conclusion, these studies provide a first look at the role of OGT signaling in the alpha-cell, its effect on alpha-cell mass, and its importance in regulating glucagon secretion in hypoglycemic conditions.

Insulin-secreting pancreatic β-cells express proteins characteristic of D-serine regulated synapses, but the acute effect of D-serine co-agonism on its presumptive β-cell target, N-methyl D-aspartate receptors (NMDARs), is unclear. We used multiple models to evaluate glucose homeostasis and insulin secretion in mice with a systemic increase in D-serine (intraperitoneal injection or DAAO mutants without D-serine catabolism) or tissue-specific loss of Grin1-encoded GluN1, the D-serine binding NMDAR subunit. We also investigated the effects of D-serine ± NMDA on glucose-stimulated insulin secretion (GSIS) and β-cell depolarizing membrane oscillations, using perforated patch electrophysiology, in β-cell-containing primary isolated mouse islets. In vivo models of elevated D-serine correlated to improved blood glucose and insulin levels. In vitro, D-serine potentiated GSIS and β-cell membrane excitation, dependent on NMDAR activating conditions including GluN1 expression (co-agonist target), simultaneous NMDA (agonist), and elevated glucose (depolarization). Pancreatic GluN1-loss females were glucose intolerant and GSIS was depressed in islets from younger, but not older, βGrin1 KO mice. Thus, D-serine is capable of acute antidiabetic effects in mice and potentiates insulin secretion through excitatory β-cell NMDAR co-agonism but strain-dependent shifts in potency and age/sex-specific Grin1-loss phenotypes suggest that context is critical to the interpretation of data on the role of D-serine and NMDARs in β-cell function.

We report on the development and extensive characterization of co-sputtered tantala–zirconia (Ta 2 O 5 -ZrO 2 ) thin films, with the goal to decrease coating Brownian noise in present and future gravitational-wave detectors. We tested a variety of sputtering processes of different energies and deposition rates, and we considered the effect of different values of cation ratio η = Zr/(Zr + Ta) and of post-deposition heat treatment temperature T a on the optical and mechanical properties of the films. Co-sputtered zirconia proved to be an efficient way to frustrate crystallization in tantala thin films, allowing for a substantial increase of the maximum annealing temperature and hence for a decrease of coating mechanical loss φ c . The lowest average coating loss was observed for an ion-beam sputtered sample with η = 0.485 ± 0.004 annealed at 800 °C, yielding φ ¯ c = 1.8 × 1 0 − 4 rad. All coating samples showed cracks after annealing. Although in principle our measurements are sensitive to such defects, we found no evidence that our results were affected. The issue could be solved, at least for ion-beam sputtered coatings, by decreasing heating and cooling rates down to 7 °C h −1 . While we observed as little optical absorption as in the coatings of current gravitational-wave interferometers (0.5 parts per million), further development will be needed to decrease light scattering and avoid the formation of defects upon annealing.

During early obesity, pancreatic β cells compensate for increased metabolic demand through a transient phase of insulin hypersecretion that stabilizes blood glucose and forestalls diabetic progression. We find evidence that β cell O-GlcNAcylation, a nutrient-responsive post-translational protein modification regulated by O-GlcNAc transferase (OGT), is critical for coupling hyperlipidemia to β cell functional adaptation during this compensatory prediabetic phase. In mice, islet O-GlcNAcylation rises and falls in tandem with the timeline of secretory potentiation during high-fat feeding while genetic models of β-cell-specific OGT loss abolish hyperinsulinemic responses to lipids, in vivo and in vitro. We identify the endoplasmic reticulum (ER) Ca2+ ATPase SERCA2 as a β cell O-GlcNAcylated protein in mice and humans that is able to rescue palmitate-stimulated insulin secretion through pharmacological activation. This study reveals an important physiological role for β cell O-GlcNAcylation in sensing and responding to obesity, with therapeutic implications for managing the relationship between type 2 diabetes and its most common risk factor.

Protein translation is essential for cell physiology, and dysregulation of this process has been linked to aging-related diseases such as type 2 diabetes. Reduced protein level of a requisite scaffolding protein of the initiation complex, eIF4G1, downstream of nutrients and insulin signaling, is associated with diabetes in both humans and mice. In the present study, we tested the hypothesis that eIF4G1 is critical for β-cell function and glucose homeostasis by genetically ablating eIF4G1 specifically in β-cells in vivo (βeIF4G1KO). Adult male and female βeIF4G1KO mice displayed glucose intolerance but normal insulin sensitivity. β-cell mass was normal under steady state and under metabolic stress by diet-induced obesity, but we observed increases in both proliferation and apoptosis in β-cells of βeIF4G1KO. We uncovered deficits in insulin secretion, partly due to reduced mitochondrial oxygen consumption rate, glucose-stimulated Ca2+ flux, and reduced insulin content associated with loss of eIF4E, the mRNA 5'-cap binding protein of the initiation complex and binding partner of eIF4G1. Genetic reconstitution of eIF4E in single β-cells or intact islets of βeIF4G1KO mice recovers insulin content, implicating an unexplored role for eIF4G1/eIF4E in insulin biosynthesis. Altogether these data demonstrate an essential role for the translational factor eIF4G1 on glucose homeostasis and β-cell function.

Amorphous tantala (Ta2O5) thin films were deposited by reactive ion beam sputtering with simultaneous low energy assist Ar+ or Ar++O2+ bombardment. The films absorption and mechanical losses are not significantly affected by the ion bombardment.

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Brownian thermal noise in dielectric multilayer coatings limits the sensitivity of current and future interferometric gravitational wave detectors. In this work we explore the possibility of improving the mechanical losses of tantala, often used as the high refractive index material, by depositing it on a substrate held at elevated temperature. Promising results have been previously obtained with this technique when applied to amorphous silicon. We show that depositing tantala on a hot substrate reduced the mechanical losses of the as-deposited coating, but subsequent thermal treatments had a larger impact, as they reduced the losses to levels previously reported in the literature. We also show that the reduction in mechanical loss correlates with increased medium range order in the atomic structure of the coatings using x-ray diffraction and Raman spectroscopy. Finally, a discussion is included on our results, which shows that the elevated temperature deposition of pure tantala coatings does not appear to reduce mechanical loss in a similar way to that reported in the literature for amorphous silicon; and we suggest possible future research directions.

Brownian thermal noise generated by mechanical losses in thin film coatings limits the sensitivity of gravitational wave detectors, as well as several high precision metrology experiments. Improving the sensitivity of the next generation of gravitational wave detectors will require optical coatings with significantly reduced mechanical losses. In this paper, we describe a system that we developed to measure the mechanical loss angle of thin film coatings deposited on fused silica substrates. The novelty of this system resides in the capability of parallel measurement of up to four samples and the ability to simultaneously probe all the resonant modes of each sample. This high throughput measurement system allows the exploration of a large number of deposition and material parameters, which can be tuned to achieve low loss coatings.

D-serine is present in the vertebrate retina and serves as a coagonist for the N-methyl-D-aspartate (NMDA) receptors of ganglion cells. Although the enzyme D-amino acid oxidase (DAO) has been implicated as a pathway for d-serine degradation, its role in the retina has not been established. In this study, we investigated the role of DAO in regulating D-serine levels using a mutant mouse line deficient in DAO (ddY/DAO(-)) and compared these results with their wild-type counterparts (ddY/DAO(+)). Our results show that DAO is functionally present in the mouse retina and normally serves to reduce the background levels of D-serine. The enzymatic activity of DAO was restricted to the inner plexiform layer as determined by histochemical analysis. Using capillary electrophoresis, we showed that mutant mice had much higher levels of D-serine. Whole cell recordings from identified retinal ganglion cells demonstrated that DAO-deficient animals had light-evoked synaptic activity strongly biased toward a high NMDA-to-AMPA receptor ratio. In contrast, recordings from wild-type ganglion cells showed a more balanced ratio between the two receptor subclasses. Immunostaining for AMPA and NMDA receptors was carried out to compare the two receptor ratios by quantitative immunofluorescence. These studies revealed that the mutant mouse had a significantly higher representation of NMDA receptors compared with the wild-type controls. We conclude that 1) DAO is an important regulatory enzyme and normally functions to reduce D-serine levels in the retina, and 2) D-serine levels play a role in the expression of NMDA receptors and the NMDA-to-AMPA receptor ratio.

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