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Type 2 inflammation plays a critical role in most asthmatic cases and may be affected during recurring viral and bacterial infections. The presence of intracellular pathogens promotes the buildup of danger signaling cyclic-di-nucleotide molecules such as cyclic-di-GMP (CDG), a bacterial second messenger. Group 2 innate lymphoid cells (ILC2s) are major contributors to type 2 inflammatory responses after exposure to fungal allergens yet the role of CDG in regulating pulmonary ILC responses in inflammation remains to be seen. Our studies demonstrate that intranasal exposure to CDG drives early type 1 interferon (IFN) production and effectively suppresses type 2 lung inflammation and CD127+ST2+ ILC2s during Alternaria challenge in a STING-cGAS dependent manner. Interestingly, CDG drove activation and expansion of ST2-CD127- pulmonary ILCs, which exhibit a transcriptomic profile consistent with ILC1s. Overall, CDG has demonstrated a suppressive effect on type 2 inflammatory responses while simultaneously promoting ILC1 activation. Our findings suggest that there is potential to utilize STING to mediate type 2 inflammatory responses and/or promote anti-viral immunological mechanisms.

Introduction: Randomized controlled trials and real-world data from the USA have shown similar glycemic control with insulin glargine 300 U/ml (Gla-300) and insulin glargine 100 U/ml (Gla-100) and reduced hypoglycemia risk with Gla-300. This real-world study describes the efficacy and safety of Gla-300 and Gla-100 in patients with type 2 diabetes (T2D) in France, Spain, and Germany. Methods: This retrospective chart review analysis used anonymized data for adults with T2D switching basal insulin analog (BIA) therapy to Gla-300 or Gla-100, or insulin-naïve patients initiating Gla-300 or Gla-100. Outcomes included change from baseline to 6-month follow-up in glycated hemoglobin A1c (A1C), total and severe hypoglycemia incidences and events, insulin dose, and reasons for BIA choice. Results: Six hundred sixty-five physicians (33.8% Spain, 31.7% France, 34.4% Germany) provided chart data for patients switching to Gla-300 (n = 679) or Gla-100 (n = 429) or initiating Gla-300 (n = 719) or Gla-100 (n = 711). After adjustment for baseline characteristics, A1C reductions from baseline were similar for patients switching to Gla-300 or Gla-100 (- 0.87% vs. - 0.93%; p = 0.326) while those switched to Gla-300 vs. Gla-100 had a significantly greater mean reduction in hypoglycemic events (- 1.29 vs. - 0.81 events during 6 months; p = 0.012). Mean insulin doses after titration were 0.43 ± 0.36 and 0.40 ± 0.28 U/kg in Gla-300 and Gla-100 switchers, respectively. Factors that significantly influenced BIA choice included a lower risk of hypoglycemia (for Gla-300) and physician familiarity (for Gla-100). Outcomes for insulin-naïve patients were broadly similar to those of switchers. Conclusions: In this real-world European study, patients with T2D who switched therapy to Gla-300 or Gla-100 had improved glycemic control and reduced hypoglycemia at 6 months, with significant hypoglycemia advantages with Gla-300.

In adult mammals, beige fat is recruited in response to environmental cold in order to generate heat (thermogenesis) and maintain a constant body temperature. It is also transiently and physiologically induced in postnatal animals; however, little is known about how this process is regulated. Here, we use light sheet microscopy, high throughput sequencing, and metabolic assays to show that although the spatiotemporal kinetics of recruitment are very similar in young and adult mice, distinct regulatory signals prevail at each time point. Systemic adrenergic signaling or environmental cold stimulus is required only for beiging in adult, but not postnatal animals. In contrast, postnatal beiging depends on tissue- and cell-intrinsic pathways such as type 2 cytokines and adipocyte B-cell lymphoma 6 (BCL6) respectively. In adults, BCL6 is required for neither transdifferentiation of naïve adipocytes, nor reactivation of dormant cells. Together, our findings reveal an unexpected distinction between beige fat regulation in postnatal and adult animals, thereby introducing a previously-unappreciated temporal dimension to the study of the beiging process.

Only one in eight adults with diabetes reaches target goals for disease management, which can lead to clinical complications, costly both economically and in quality and duration of human life. The standard of care is a quarterly 15-minute face-to-face visit-- arguably inadequate to impart self-care knowledge. The purpose of this EBP project was to deliver a 30-day diabetes self-management education program (DSMEP) utilizing widely accessible web-based technology to facilitate adults with diabetes to reach targeted goals. Using the Chronic Care Model as a framework, the DSMEP design was based on an extensive literature review of the delivery of DSMEP in an asynchronous manner via web-enabled devices. The program consisted of two daily short messages of diabetes self-management content with two-way message capability allowing participants to respond or seek clarification. Participants’ (N = 16) pre-DSMEP A1C values were converted to an estimated average glucose (eAG) value using the A1C Average Glucose Study Group formula, which were compared to their 30-day DSMEP mean blood glucose values using a paired t-test. A RM-ANOVA was performed to determine at what point in the DSMEP blood glucose values had the most significant improvement. Participants completed a pre- and post-intervention Diabetes Self- Management Questionnaire (DSMQ), allowing for comparison of self-reported selfmanagement skills using a paired t-test. The pre-intervention eAG was 193.8 (sd = 38.58), and the post-intervention mean glucose value was 151.9 (sd = 28.07) (t = -41.85, p < .001). The pre- and post-intervention DSMQ sum scale and glucose monitoring control subscale results showed statistically significant improvement. Improvements were also noted in dietary management and physical activity behaviors. Results indicate that a DSMEP delivered from a patient portal to a web-enabled device is an effective way to significantly improve the mean daily blood glucose value of the adult with diabetes type 2 and improvement in self-reported diabetes self-management skills.

Understanding the relationships between culture, associated health beliefs and lifestyle, and ethnic disparities in health is of particular importance in Australia, where one in four people was born overseas. Vietnam-born Australians (N=159,849 at the 2006 Census) are among the top five overseas-born population groups. Most arrived as refugees (50%, 1977-1986) and family reunion immigrants (42%, 1987-1996), thus many have poorer socio-economic status than other population groups. Vietnam-born Australians also share a distinct Oriental culture and traditional health beliefs that largely differ from Western biomedicine perspectives. Changes in diet among new immigrants have been reported but the impact of acculturation on various lifestyle factors and, importantly, health status of Vietnam-born Australians has not been examined extensively. Research evidence shows that people of Vietnamese ethnicity are at higher risk of diabetes. However, there is little existing information about diabetes among Vietnam-born Australians. Therefore, this thesis aimed to investigate two interrelated aspects of health in this population: the impact of acculturation on health-related behaviours and health status; and the prevalence of type 2 diabetes, its risk factors and hospitalisation and mortality outcomes. Baseline questionnaire data (2006 to 2008) from the 45 and Up Study, a cohort study of more than 266,000 residents of New South Wales (NSW), Australia aged 45 years and over, were used to investigate relationships between acculturation (duration of residence, age at immigration, density of Vietnam-born population in residential areas, and social interactions) and lifestyle, health status, and prevalence of and risk factors for type 2 diabetes. Analytic techniques included descriptive statistics, direct age-standardisation and logistic regression modelling. Among 797 Vietnam-born participants in the Study (390 men and 407 women), higher levels of acculturation were associated with increased consumption of red meat, white meat and seafood, higher levels of physical activities, and lower prevalence of overweight and obesity, and type 2 diabetes. Likelihood of smoking was lower among Vietnam-born men living in areas with low proportion of Vietnam-born population (< 2%). The age standardised prevalence of self-reported type 2 diabetes was 11.2% (crude prevalence 12.9%), which was 1.6 times (95%CI=1.31-1.90) higher than in Australia-born participants. Strong risk factors for type 2 diabetes in Vietnam-born participants included family history of diabetes (adjusted odds ratio [OR]=7.07, 95%CI=4.14-12.07) and older age (OR≥2.49, p< 0.001). Overweight or obesity based on body mass index (≥23.0 kg/m2) was not a strong predictor (OR=1.64, 95%CI=0.99-2.74). Vietnam-born people with type 2 diabetes were more likely to have a health care concession card, high blood pressure, heart disease, and poorer self-rated general health and quality of life. The NSW Admitted Patient Data Collection (APDC, 1/7/2000 to 31/12/2008), an administrative database of all hospital stays in NSW, was linked to NSW death registrations (1/7/2000 to 30/12/2009) and Australian Bureau of Statistics mortality data (1/7/2000 to 30/12/2007) to investigate diabetes-related hospitalisation and mortality. One hundred and fifty-two Vietnam-born patients admitted between 1/7/2000 and 31/12/2008 for treatment of type 2 diabetes were followed prospectively for readmissions and mortality. Statistical techniques included Poisson and Cox proportional hazard regression modelling. Vietnam-born patients had lower rates of readmission for diabetes and comorbidities (450.7, 95%CI=394.4-515.0 per 1,000 person-years) than Australia-born counterparts (528.5, 95%CI=522.2-535.0) but the difference was not statistically significant (adjusted rate ratio [RR]=0.81, 95%CI=0.64-1.03). However, Vietnam-born patients had significantly higher risk of death from all causes (adjusted hazard ratio [HR]=1.42, 95%CI=1.07-1.88) and for diabetes-related causes (HR=1.58, 95%CI=1.05-2.38). The prevalence of hypertension, chronic kidney disease, and other comorbidities was significantly higher in Vietnam-born than in Australia-born patients. The findings of this thesis have implications for education about healthy lifestyle and for proactive management of diabetes in this population. Early diagnosis and optimal control of diabetes and comorbid conditions are important for Vietnam-born Australians given their high risk of diabetes. Family members’ participation in patient-centred management of people with diabetes could provide additional positive outcomes. This research has demonstrated the value of record linkage of already available, population-based health administrative data for investigating diabetes management and associated health outcomes among overseas-born Australians.

Purpose: The incidence of type 2 diabetes is reaching epidemic levels. Today type 2 diabetes is the most common form of diabetes, accounting for 85 to 90 percent of diabetes cases. The James Lab at Garvan Institute for Medical Research are interested in gene expression in insulin resistance and diabetes. They have provided three gene expression data sets: a longitudinal mouse study involving the comparison of a high-fat diet to a standard diet with gene expression in two tissues, a mouse cell line study and a cross-sectional human study. The main goals of this research is to identify differentially expressed genes in both the mouse and human data, compare genomic expression patterns across species, human and mouse, and to focus on pathway analysis for detecting differential expression in predefined gene sets based on Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Methods: Three data sets are normalized in order to remove experimental effects arising from the microarray technology. Linear models can then be fitted on the normalized data using the limma package to identify genes undergoing differential expression. Each gene has its own expression profile and genes with similar profiles can be grouped together. We intend to try and use the data sets together to cluster samples based on gene profiles. In reality, biological processes are complicated with many molecules working together. The goal of annotating the genome is to link all information associated with gene products in order to learn how pathways function in the biological system. In situations where long lists of genes are found to be differentially expressed, we consider focusing on the analysis of gene sets because it is more sensible to investigate gene sets that are functionally related based on prior biological knowledge or experiments. We explore the potentially interesting gene sets using the Gene Ontology (GO) database and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Differentially expressed genes detected in the mouse data are mapped to their corresponding gene sets based on the Gene Ontology terms and KEGG pathways. Competitive and self-contained gene set tests (the mean-rank gene set test and the rotation gene set test) are performed for each comparison in the human data. The correlation adjusted mean-rank gene set test is included in testing insulin or glucose related GO terms and KEGG pathways. To test if any GO terms (Biological Process) or KEGG pathways are over-represented in a list of differentially expressed genes in the mouse or human data sets, we carry out the hypergeometric test. Results: We identify a large number of differentially expressed genes in the muscle tissue from the longitudinal mouse study. The cross-species gene set tests have revealed significant GO terms and KEGG pathways in each condition of obese patients relative to healthy controls. We compare the results produced by the mean-rank gene set test and the rotation gene set test. Significant insulin or glucose related gene sets are found using three gene set testing methods and the results are compared. The FOXO gene set is found to be significantly up-regulated in two contrasts in the human data.

The main study purposes were to determine: whether antidepressant (AD) use increases the risk of type 2 diabetes mellitus; and whether results differ when using different methodological designs: retrospective cohort design and nested case-control design. A retrospective Texas Medicaid database analysis of new AD (exposed cohort) and benzodiazepine (unexposed cohort [BZ]) users from January 1, 2002 to December 31, 2009 was conducted. Patients aged 18-64 years without diabetes at cohort entry were included. The primary outcome was incident diabetes and the main independent variable was AD vs. BZ use. Covariates included age, gender, race/ethnicity, medication adherence, persistence, number of concomitant diabetogenic medications, Chronic Disease Score, treatment duration, year of cohort entry, and use of both AD and BZ at index. Regression analyses (adjusted) were used to address the study purposes. Of the study cohort (N=44,715), 35,552 (79.5%) were AD users and 9,163 (20.5%) were BZ users. Patients were followed for an average of 2.3±1.9 years (Median=1.8 years), were on average 38.6±14.2 years old, and 69.3% were female. Using the retrospective cohort design, AD use was associated with a 48.9% increase (logistic regression) and 60.0% increase (Cox regression) in the risk of diabetes compared to BZ use (logistic regression analysis: RR[subscript adj]. =1.489; 95% CI: 1.331-1.667; Cox regression analysis: HR[subscript adj]. =1.600; 95% CI: 1.437 - 1.783). Using a nested case-control design within the entire study cohort, AD use was associated with a 54.1% increase in the risk of diabetes compared to BZ use (OR[subscript adj]. =1.541; 95% CI: 1.368 - 1.735). Using a nested case-control design within the exposed cohort, current AD use was associated with a two-fold higher risk of diabetes compared to former AD use (OR[subscript adj]. =1.995; 95% CI: 1.759 - 2.264). Among antidepressant classes, TCAs, SSRIs, SNRIs, and Other ADs were associated with a higher diabetes risk compared with BZs. The results from the present study suggest that AD use is associated with an increased risk of diabetes. Clinicians may need to take this into account when choosing treatment for depression in patients at high risk of diabetes.

The purpose of this study was to describe the process by which persons with type 2 diabetes mellitus self-manage their disease. Diabetes, a chronic disease, requires complex, individual, long-term self-management. Grounded theory methods were used to develop a theoretical framework. Participation criteria included adults over 18 who had a diagnosis of type 2 diabetes mellitus of one to two years and had participated in a Diabetes Self-Management Skills and Training (DSMT) program. A selective sample of 21 participants was recruited from health care facilities in Northeast Ohio. Dealing with Type 2 Diabetes was identified as the psychosocial problem shared by participants. The psychosocial process for this problem was called Evolving Diabetes Self. The psychosocial process of Evolving Diabetes Self encompasses four phases with interrelated categories within each phase that impact the psychosocial problem of Dealing with Type 2 Diabetes. The four phases are as follows: (a) Getting the Diagnosis, (b) Realizing Options, (c) Making Decisions, and (d) Living the Consequences.This study provided a theoretical framework for describing the processes by which individuals with type 2 diabetes manage their disease. Type 2 diabetes is a chronic disease requiring complex and lifelong changes. Health care providers are in an integral position to facilitate change from an acute care emphasis to a chronic care framework within organizations (insurance, hospitals, and out-patient departments) as well as to change policies and reimbursement protocols for care of diabetics.