acase@tulane.edu / Although men with testosterone deficiency are at increased risk for type 2 diabetes (T2D), previous studies have ignored the role of testosterone and the androgen receptor (AR) in pancreatic β–cell. Our study shows that male pancreatic β–cell specific AR knockout (βARKOMIP) mice develop glucose intolerance because AR potentiates glucose-stimulated insulin secretion (GSIS) through increasing cyclic AMP (cAMP) accumulation and amplifying the insulinotropic effect of glucagon-like peptide-1 (GLP-1). Using transcriptome analysis, we find that AR-deficient islets exhibit altered expression of genes involved in inflammation and insulin secretion demonstrating the importance of androgen action in β-cell health in the male. Our recent study shows that male βARKOMIP mice exhibit impaired intraperitoneal (IP) glucose tolerance- because of impaired IP-GSIS- without alteration in oral glucose tolerance, suggesting that AR amplifies the islet-derived, but not the gut-derived GLP-1 to potentiate GSIS. Dihydrotestosterone (DHT) increases the insulinotropic effect of GLP-1, not gastric inhibitory polypeptide (GIP) and glucagon, in male insulin-secreting β-cell line 832/3 cells and wild-type male mouse islets. Accordingly, using 832/3 cells transduced with exchange factor directly activated by a cAMP (EPAC)-based fluorescence resonance energy transfer (FRET) sensor, we observe that the AR agonist dihydrotestosterone (DHT) specifically allows GLP-1, not GIP and glucagon, to increase cAMP production above level of the individual hormones. The insulinotropic effect of DHT is abolished using EPAC and PKA inhibitors as well as rapamycin indicating that DHT stimulates GSIS via a cAMP/PKA/EPAC pathway and activation of mTOR. This study identifies AR as a novel receptor that enhances β–cell function, a finding with implications for the prevention of type 2 diabetes (T2D) in aging men. / 1 / Weiwei Xu

Thesis Title Exploring new methodologies to identify disease-associated variants in African populations through the integration of patient genotype data and clinical phenotypes derived from routine health data: A case study for Type 2 Diabetes Mellitus patients in the Western Cape Province, South Africa. Abstract Introduction There is poor knowledge on the genetic drivers of disease in African populations and this is largely driven by the limited data for human genomes from sub-Saharan Africa. While the costs of generating human genomic data have gone down significantly, they are still a barrier to generating large scale African genomic data. This project is therefore a proof-of-concept pilot study that demonstrates the implementation of a cost-effective, scalable genotyped virtual cohort that can address population level genomic questions. Methods We optimised a tiered informed consent process that is suitable for the cohort study design and adapted it to conducting human genomic research in the African context. We used an existing dataset to explore statistical methods for modelling longitudinal routine health data into a standardised phenotype for genome wide association studies (GWAS). We then conducted a feasibility study and piloted the tiered informed consent process, DNA collection by buccal swab and DNA extraction from buccal swabs and peripheral blood samples. DNA samples were genotyped for approximately 2.2 million variants on the Infinium™ H3Africa Consortium Array V2. Genotyping quality control (QC) was done in Plink 1.9 and genome wide imputation on the Sanger Imputation Service. We demonstrated successful variant calling and provide aggregate statistics for known aetiological variants for type 2 diabetes and severe COVID-19 as well as demonstrating the feasibility of running nested case-control GWAS with these data. Results We demonstrate the use of routine health data to provide complex phenotypes to link to genotype data for both non-communicable diseases (diabetes) and infectious diseases (Tuberculosis, HIV and COVID-19). 459 participants consented to providing a DNA sample and access to their routine health data and were included in the feasibility study. A total of 343 DNA samples and 1782023 genotyped variants passed quality control and were available for further analysis. While most of the cohort population clustered with the 1000 genomes African population, principal component analysis showed extensive population admixture. For the COVID-19 analysis, we identified 63 cases of severe COVID-19 and 280 controls, and for the type 2 diabetes analysis we identified 93 cases and 250 controls using the routine health data of participants in the cohort. While the sample sizes were insufficient for a GWAS we were able to evaluate known type 2 diabetes mellitus and COVID-19 variants in the study population. Conclusion We have described how we conceptualised and implemented a genotyped virtual population cohort in a resource constrained environment, and we are confident that this design and implementation are appropriate to scale up the cohort to a size where novel health discoveries can be made through nested case-control studies. In the interim we demonstrate the analysis and validation of aetiological variants identified in other studies and populations.

This thesis begins with a background chapter which explores the current diabetes epidemic and examines the role of obesity and oxidative stress as causative factors. Current dietary recommendations for prevention of type 2 diabetes are critically evaluated. A systematic review and meta-analysis was conducted to determine the independent role of fruit and vegetables in preventing diabetes. Convincing benefit for greater consumption of green leafy vegetables was demonstrated. An insignificant trend towards benefit was observed for fruit and vegetables. The Fruit and Vegetable Intake and Glucose Control Study (FIVE) is a sub study of the Let’s Prevent Diabetes Study. FIVE includes cross sectional analysis of baseline plasma vitamin C, (a biomarker for fruit and vegetable intake) from 2101 participants. FIVE further includes 12 months analysis of individuals with impaired glucose regulation, randomised to receive group education or usual care. Results demonstrate 29% of the population consumed at least 5 portions of fruit and vegetables a day. Fewer South Asian individuals met the recommendation compared to White Europeans (21% vs. 30% p = 0.003). Each additional piece of fruit or vegetable consumed (21.8μmol/l plasma vitamin C) was associated with a reduction of 0.04% in HbA1c, 0.05mmol/l in fasting and 0.22mol/l in 2 hour blood glucose. Participants who consumed 5 portions a day compared to those who did not, had a 24% associated reduced risk of being diagnosed with impaired glucose regulation (OR = 0.76, 95% CI: 0.59 to 0.98). At 12 months follow up those receiving lifestyle education had greater levels of plasma vitamin C compared to those in the usual care arm (36.1μmol/l (SD 20.7) vs.29.9μmol/l (SD 20.3)). No statistical difference in mean change between intervention arms was seen. The thesis provides novel, robust nutritional biomarker data from a large at risk, multi ethnic population. Results support recommendations to promote fruit and vegetables in the diet to prevent diabetes. The potential for tailored advice on increasing green leafy vegetables among those at risk of diabetes should be investigated further.

Background: Exercise is widely recognized as the cornerstone of management of type II diabetes (T2D). However, it is also known that people with T2D have poor adherence to exercise regimens, which is largely thought to be because of poor exercise tolerance. Recent studies have suggested that this exercise intolerance may be caused by a reduction in exercising muscle blood flow. One physiological mechanism which could potentially contribute is the muscle metaboreflex (MMR). This mechanism is thought to be a pressure-based flow-improving mechanism, but as a result of reduced efficacy of vasodilators and sympatholytic agents, might in fact be restraining the flow-improvement in persons with T2D. Hypothesis: Persons with T2D would not improve exercising muscle blood flow upon MMR activation. This absence of flow-improvement will be due to an augmented vasoconstriction in the exercising muscle. Methods: T2D (n=7) and CTL (n=6) participants performed rhythmic forearm handgrip exercise at an intensity equivalent to 20% MVC for 9 minutes with and without the application of ischemic plantar flexion (IPF). Forearm blood flow (FBF), mean arterial pressure (MAP), cardiac output (CO), heart rate (HR), total peripheral resistance (TPR) and forearm vascular conductance (FVK) were quantified for the last thirty seconds of each of four time points during the protocol. Plasma norepinephrine was measured via deep venous and arterialized venous blood sampling. Results: Steady state exercising FBF was increased in CTL but not in T2D during MMR activation (mean ± SE mL/min: CTLControl 161.16 ± 5.95, CTLMMR 212.72 ± 9.49, T2DControl 156.71 ± 13.08, T2DMMR 144.22 ± 10.55). This occurred despite similar increases in MAP, CO, HR, and TPR (across groups and treatment conditions, NS). FVK increased in CTL during the MMR protocol compared to the Control protocol, but decreased in the T2D group using the same comparison (mean ± SE mL/min/100 mm Hg: CTLControl 144.74 ± 5.63, CTLMMR 176.76 ± 11.99, T2DControl 143.29 ± 13.44, T2DMMR 103.53 ± 8.44). Conclusions: In the exercise model utilized, persons with T2D do not demonstrate the MMR-induced flow improvement seen in CTL. This impaired muscle blood flow in T2D is the result of MMR induced exercising limb vasoconstriction. / Thesis (Master, Kinesiology & Health Studies) -- Queen's University, 2012-01-31 09:30:42.604

No description available.

Alzheimer’s disease (AD) is the most reoccurring type of dementia, and remains incurable. Much work has been done to investigate the connections between AD development, type 2 diabetes and insulin receptor signaling abnormalities. Full length amyloid precursor protein (flAPP) is a large transmembrane protein that has significant physiological activities including in utero fetal development. Alpha secretase enzymes cleave flAPP, producing secreted amyloid precursor protein alpha (sAPPα), which has neuroprotective properties, including protection against neuronal apoptosis as well as the induction of neuronal outgrowth. There is no known dedicated receptor for the physiological action of sAPPα. Our data suggest that the physiological actions of sAPPα are a result of the physical interaction between sAPPα and the neuronal insulin receptor. We have shown that sAPPα phosphorylates, and thus activates, the neuronal insulin receptor as well as specific downstream proteins, including insulin receptor substrate (IRS), and protein kinase B (Akt). We have also shown that the observed interaction between sAPPα and neuronal insulin receptors is physical and that sAPPα competes with insulin for the insulin binding site. These findings may have implications for therapies aimed at slowing down the progression of AD through the activation of the insulin receptor pathway, since in neurons, insulin and the insulin receptor pathway are critical to the neuronal health and plasticity.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2006. / Härtill 4 uppsatser.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2009. / Härtill 6 uppsatser.

AN ABSTRACT OF THE THESIS OF Sarah Sheffer, for the Master of Science degree in Food and Nutrition, presented on September 3, 2009, at Southern Illinois University Carbondale. TITLE: "R. U. A. HEALTHY KID?"- NON-INVASIVE SCREENING FOR RISK FACTORS FOR TYPE 2 DIABETES AT VIENNA GRADE SCHOOL MAJOR PROFESSOR: Dr. Sharon Peterson It is estimated that 1 in 3 children born after the year 2000 will develop some form of diabetes (CDC, 2007). Through Public Act 92-0703, the state of Illinois has started requiring screening for T2DM at the 6th and 9th grade school physicals following the ADA guidelines (IDHS, 2006). The ADA recommends screening children ten and older with a BMI ≥ 85th percentile for two additional risk factors for T2DM (ethnic minority, positive family history of T2DM, hypertension, acanthosis nigricans) (ADA, 2000). While much research has been done, few studies in the U.S. have looked at traditionally "low risk" populations (Sinha 2002, Whitaker 2004, Arslanian 2005). Our study sought to further understand the prevalence of risk factors in a predominantly Caucasian elementary school (K-8 grade). Our study (N=299) found approximately 67% of students to have 1 or more risk factors for T2DM and classified 17 students "at risk" for T2DM. Following Illinois Public Act 92-0703, only 1 student would have been identified "at risk" for T2DM. When comparing "at risk" status, all risk factors except ethnicity were found statistically significant (p< 0.001). Hypertensive "at risk" students were more likely to be morbidly obese (p< 0.001). Our study also found more risk factors as BMI increased.

The cross sectional study investigated the association of tobacco smoke, vitamin D status, anthropometric parameters, and kidney function in Turkish immigrants with type 2 diabetes (T2D) living in the Netherlands. Study sample included a total of 110 participants aged 30 years and older (males= 46; females= 64). Serum cotinine, a biomarker for smoke exposure, was measured with a solid-phase competitive chemiluminescent immunoassay. Serum 25-hydroxyvitamin D [25(OH)D] was determined by electrochemiluminescence immunoassay (ECLIA). Measures of obesity including: body weight, body mass index (BMI), waist circumference (WC), and hip circumference (HC) were measured. Waist-to-hip ratio (WHR) and waist-to-height ratio (WHtR) were calculated. Urine albumin was measured by immunoturbidimetric assay. Urine creatinine was determined using the Jaffe method. All statistical analyses were performed using SPSS, version 19.0 (SPSS Inc., Chicago, IL, USA). Independent samples t-test, chi-squared tests, multiple linear regression and logistic regression analysis were used. Cotinine levels were positively associated with cholesterol to HDL ratio and atherosclerosis-index. Serum 25(OH)D levels were negatively associated with diastolic blood pressure. Gender-specific associations between anthropometric measures and high sensitivity C-reactive protein (hs-CRP) levels were observed. Hs-CRP was positively associated with WC and WHR in males and WHtR in females. Microalbuminuria (MAU), as determined by albumin-to-creatinine ratio, was present in 21% of the Turkish immigrants with T2D. Participants with hypertension were 6.58 times more likely (adjusted odds ratio) to have positive MAU as compared to normotensive participants. Our findings indicate that serum cotinine, 25(OH)D, hs-CRP, and MAU may be assessed as a standard of care for T2D management in the Turkish immigrant population. Further research should be conducted following cohorts to determine the effects of these biomarkers on CVD morbidity and mortality.