Most common diseases have substantial heritable components but are characterized by complex inheritance patterns implicating numerous genetic and environmental factors. A longstanding goal of human genetics research is to delineate the genetic architecture of these traits - the number, frequencies, and effect sizes of disease-causing alleles - to inform mapping studies, elucidate mechanisms of disease, and guide development of targeted clinical therapies and diagnostics. Although vast empirical genetic data has now been collected for common diseases, different and contradictory hypotheses have been advocated about features of genetic architecture (e.g., the contribution of rare vs. common variants). Here, we present a framework which combines multiple empirical datasets and simulation studies to enable systematic testing of hypotheses about both global and locus-specific complex trait architecture. We apply this to type 2 diabetes (T2D).

Apoptosis is an intricately regulated cellular process required for the health and homeostasis of living systems. The mitochondrial apoptotic pathway depends on the BCL-2 family of pro- and anti-apoptotic members whose interactions regulate cell fate. BAX and BAK are key pro-apoptotic proteins required for mitochondrial permeabilization during apoptosis. While the mitochondrial death program relies heavily on its protein components, evidences support equally crucial roles for lipids and lipid metabolism in promoting or hindering apoptosis at the mitochondria. To gain insight into the interplay between lipids and BCL-2 proteins we used a liquid chromatography (LC)-mass spectrometry (MS)-based comparative lipidomics approach to uncover lipid changes in the absence of BAX and/or BAK. Our analysis revealed novel functions for BAX and BAK in inflammation and ceramide metabolism. A targeted LC-MS workflow was also developed for characterization of a novel lipid class involved in type 2 diabetes. Targeted LC-MS revealed altered oxysterol metabolism following perturbation of the Sonic hedgehog pathway. Taken together, our findings demonstrate interesting connections among lipids, cell death and disease. / Chemistry and Chemical Biology

Background: Glycated hemoglobin is the indicator of long-term diabetes control and a value below 7 percent is recommended by the American Diabetes Association (ADA) to reduce cardiovascular complications. Diabetic patients have a two- to four-fold risk of cardiovascular disease and approximately two-thirds of diabetic patients die as a result of cardiovascular complications. Three large prospective randomized controlled long-term trials within the last decade reported no significant reduction in cardiovascular complications in type 2 diabetic patients by intensive glycemic control. To the author's knowledge, no known retrospective studies have examined the association between mean serial glycated hemoglobin and coronary atherosclerosis (CA) or acute coronary syndromes (ACS). Objective: This study was designed to determine the association between mean serial glycated hemoglobin with incident CA or ACS in type 2 diabetic patients after controlling for age, gender, hypertension, low density lipoprotein cholesterol (LDL-C), microalbuminuria, aspirin use, statin use, insulin use, tobacco use, and body mass index (BMI). Methods: The study was a retrospective cohort database analysis using the Austin Travis County CommUnityCare[trademark] clinics' electronic medical record for the time period between October 1, 2004 and September 30, 2009. The primary outcome of the study was the incidence of CA or ACS and the primary independent variable was glycated hemoglobin (<7% vs. [greater than or equal to]7%). The study subjects included type 2 diabetic patients aged 30 to 80 years with at least one glycated hemoglobin value per year for a minimum of two consecutive years. Study subjects were excluded if CA or ACS occurred within six months of the index date (i.e., first glycated hemoglobin). Logistic regression analysis was used to address the study objective. Results: Overall, 3069 subjects met the study inclusion criteria with a mean follow-up period of approximately two years. Two percent (N=62) of the subjects had incident CA or ACS. After controlling for age, gender, hypertension diagnosis, LDL-C, microalbuminuria, aspirin use, statin use, insulin use, tobacco use and BMI, there was no significant association (OR=1.026, 95% CI=0.589-1.785, p=0.9289) between mean serial glycated hemoglobin and the incident diagnosis of CA or ACS. Increasing age (OR=1.051, 95% CI=1.025-1.077, p<0.0001), male gender (OR=1.855, 95% CI=1.105-3.115, p=0.0195) and normal weight (normal or underweight compared to obese: OR=0.122, 95% CI=0.017-0.895, p=0.0438) were significantly associated with incident CA or ACS. Conclusions: Mean serial glycated hemoglobin (comparing [greater than or equal to]7% to <7%) was not significantly associated with CA or ACS over a mean follow-up period of approximately two years. Until more evidence becomes available, clinicians and diabetic patients should target glycated hemoglobin level below or close to 7 percent as recommended by the ADA soon after diagnosis while concomitantly controlling nonglycemic risk factors of cardiovascular disease (statin use, aspirin use, blood pressure control, smoking cessation and life style modification), to reduce their long-term risk of incident CA or ACS. / text

The present study involved the analyses of the Texas Medicaid prescription claims data. The population studied was made up of subjects between 10 and 18 years who had at least 2 prescriptions of the same oral antidiabetic (OAD) medication from January 1, 2006 through December 31, 2009. Twelve months’ data for each subject were analyzed. The main aim of the study was to describe OAD medication use patterns in the study population, assess trends in Medication Possession Ratio (MPR) and persistence in the study population and determine the relationship between age and MPR and between age and persistence while controlling for covariates. Results of the descriptive statistics, multiple and logistic regression analyses are reported. The average age (± SD) of the 3,109 eligible subjects was 14 (± 2) years; minority populations made up the majority (87%) of the population; 67% of the population were females; and 91% were on the OAD metformin. The overall mean MPR (± SD) for the population was 45% (± 27). A significant negative relationship between MPR and age was reported while controlling for covariates (p<0.0001). Among the covariates, white race and male were significantly associated with a higher MPR, holding other variables constant. When adherence was dichotomized (MPR < 80% and MPR >= 80%), logistic regression analysis also found that age was significantly and negatively related to MPR (p < 0.0001). In addition, the white race and male were again significantly related to a higher level of adherence, holding other variables constant. The overall mean days to non-persistence (± SD) was 108 days (± 86). Persistence was significantly and negatively associated with age, holding other variables constant (p < 0.0001). Among the covariates, white race was significantly related to longer persistence. In conclusion, adherence and persistence are generally low in the study population. Age, gender and race were significantly associated with adherence. Being younger, male, and white were significantly associated with a higher level of adherence, while being younger and white were significantly associated with longer persistence. Healthcare providers therefore need to intensify efforts to improve adherence in pediatric patients especially those at the brink of adulthood. / text

This Doctorate of Nursing Practice (DNP) Project is a program evaluation of a Motivational Interviewing (MI) Training Program provided by Southeast Arizona Health Education Center (SEAHEC). MI is a counseling style that focuses on exploring and resolving ambivalence to elicit behavior change. The purpose of this DNP Project was to: 1) describe the Motivational Interviewing Training Program provided by SEAHEC for ¡Vivir Mejor! healthcare providers; and 2) evaluate the long-term effectiveness of the MI training program by assessing: a) if program participants have retained the MI skills they learned in the training program, and b) if program participants apply these learned MI skills one-year post intervention in their encounters with patients diagnosed with T2DM. The Centers for Disease Control (CDC) Framework for Program Evaluation was used to guide this program evaluation. An online survey was administered to the ¡Vivir Mejor! healthcare providers to evaluate the MI program. Overall, based on the survey results, there was a positive response to the SEAHEC MI Training Program. The results of this program evaluation are limited due to a low response rate. However, these results will be shared with key stakeholders to inform the development of future MI training programs for rural healthcare providers.

Η αντίσταση στην ινσουλίνη και η απώλεια της πρώτης φάσης έκκρισης της ινσουλίνης σε απάντηση στην ενδοφλέβια χορήγηση γλυκόζης είναι οι δύο κύριες και πρωιμότερες διαταραχές στην φυσική εξέλιξη του σακχαρώδους διαβήτη τύπου 2. Στην παρούσα μελέτη διερευνήθηκε αν η απώλεια σωματικού βάρους μετά από χειρουργική επέμβαση για νοσογόνο παχυσαρκία σε ασθενείς με κλινικά σοβαρή παχυσαρκία και σακχαρώδη διαβήτη τύπου 2 μπορεί να αποκαταστήσει ευγλυκαιμία και φυσιολογική οξεία φάση έκκρισης ινσουλίνης σε ενδοφλέβια δοκιμασία ανοχής γλυκόζης (IVGTT). Μελετήθηκαν 25 ασθενείς με κλινικά σοβαρή παχυσαρκία – δώδεκα με σακχαρώδη διαβήτη τύπου 2, πέντε με παθολογική ανοχή γλυκόζης και οκτώ με φυσιολογική ανοχή γλυκόζης – πριν και μετά από χολοπαγκρεατική εκτροπή με Roux-en-Y γαστρική παράκαμψη. Δώδεκα άτομα με φυσιολογικό δείκτη μάζας σώματος ορίσθηκαν ως μάρτυρες. Δώδεκα μήνες μετά το χειρουργείο, στην ομάδα των ασθενών με σακχαρώδη διαβήτη τύπου 2, ο δείκτης μάζας σώματος μειώθηκε από 53,2 ± 2,0 σε 29,2 ± 1,7 kg/m2 , η γλυκόζη νηστείας ελαττώθηκε από 172,2 ± 15,1 σε 81,8 ± 2,4 mg/dl και η ινσουλίνη νηστείας μειώθηκε από 28,1 ± 4,3 σε 6,3 ± 0,7 μU/ml (mean ± SE, p<0,001). Η πρώτη φάση έκκρισης ινσουλίνης, η μέση τιμή συγκέντρωσης ινσουλίνης στα δύο, τρία και πέντε λεπτά μείον την βασική τιμή στην ενδοφλέβια δοκιμασία ανοχής γλυκόζης, αυξήθηκε κατά 770% και 935% στους τρεις και δώδεκα μήνες μετεγχειρητικά, αντίστοιχα (από 6,0 ± 3,8 σε 34,8 ± 7,2 και 41,3 ± 5,5 μU/ml, αντίστοιχα, p<0,001). Αντίθετα, στην ομάδα ασθενών με φυσιολογική ανοχή γλυκόζης, η πρώτη φάση έκκρισης ινσουλίνης, μειώθηκε κατά 40,5% (από 110 ± 10 σε 65,5 ± 15,5 μU/ml, p=0,027) δώδεκα μήνες μετά το χειρουργείο. Η χολοπαγκρεατική εκτροπή με Roux-en-Y γαστρική παράκαμψη στην οποία υπεβλήθησαν οι ασθενείς με κλινικά σοβαρή παχυσαρκία και σακχαρώδη διαβήτη τύπου 2 οδηγεί σε σημαντική απώλεια σωματικού βάρους, ευγλυκαιμία και φυσιολογική ευαισθησία στην ινσουλίνη, αλλά το πιο σημαντικό είναι ότι αποκαθιστά φυσιολογική πρώτη φάση έκκρισης ινσουλίνης σε απάντηση στη γλυκόζη από το β-κύτταρο και φυσιολογική σχέση οξεία φάση έκκρισης ινσουλίνης / ευαισθησία στην ινσουλίνη. Η παρούσα μελέτη είναι η πρώτη που αποδεικνύει ότι η επαγόμενη από τη γλυκόζη απολεσθείσα πρώτη φάση έκκρισης στην ινσουλίνη, στους ασθενείς με σακχαρώδη διαβήτη τύπου 2, ήπιας ή μέτριας σοβαρότητας, είναι μια αναστρέψιμη διαταραχή. Η αποκατάσταση ευγλυκαιμίας και φυσιολογικής ευαισθησίας στην ινσουλίνη φαίνεται ότι αποτελούν βασική προυπόθεση για την επανεμφάνιση φυσιολογικής πρώτης φάσης έκκρισης της ινσουλίνης. / Insulin resistance and loss of glucose-stimulated acute insulin response (AIR) are the two major and earliest defects in the course of type 2 diabetes. We investigated whether weight loss after bariatric surgery in patients with morbid obesity and type 2 diabetes can restore euglycemia and normal AIR to IV glucose tolerance test (IVGTT). We studied 25 morbidly obese patients, 12 with type 2 diabetes (DM), 5 with impaired glucose tolerance (IGT) and 8 with normal glucose tolerance (NGT) prior to and after a biliopancreatic diversion with Roux-en-Y gastric bypass (BPD with RYGBP). Twelve subjects with normal BMI served as controls. Twelve months after surgery in the DM group, BMI decreased from 53.2 + 2.0 to 29.2 + 1.7 kg/m², fasting glucose decreased from 9.5 ± 0.83 to 4.5 ± 0.13 mmol/l (mean ± SE) and fasting insulin from 168.4 ± 25.9 to 37.7 ± 4.4 pmol/l (p<0.001). AIR, the mean of insulin concentration at 2, 3 and 5 minutes over basal in the IVGTT, increased by 770% and 935% at 3 and 12 months after surgery, respectively (from 24.0 ± 22.7 pmol/l, to 209 ± 43.4 and 248 ± 33.1 pmol/l respectively) (p<0,001). Conversely, in the NGT group, the increased AIR decreased by 40.5% (from 660 ± 60 to 393 ± 93 pmol/l) (p=0.027), 12 months after surgery. BPD with RYGBP performed in morbidly obese patients with type 2 diabetes leads to significant weight loss, euglycemia and normal insulin sensitivity, but most importantly, restores a normal β-cell AIR to glucose and a normal relationship of AIR for insulin sensitivity. This is the first study, which demonstrates that the lost glucose-induced AIR, in patients with type 2 diabetes of mild or moderate severity, is a reversible abnormality. Restoration of euglycemia and normal insulin sensitivity are basal preconditions for the reappearance of normal acute insulin response to glucose.

Formation of advanced glycation endproducts (AGEs) on proteins has been linked to the pathogenesis of diabetic complications. Importantly, elevated levels of methylglyoxal (MG) occur in type 2 diabetes mellitus (T2DM), and the resulting site-specific formation of stable adducts on arginine residues can cause protein damage. Using MG, site-specific modifications on the plasma protein plasminogen (Pg) were determined following protein digestion into peptides and liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis, and 30 arginine sites were identified on the protein. Investigation into three of the most highly modified sites, R504, R530, and R561, using molecular modeling, identified likely functional changes to the Pg cleavage and the lysine binding pocket as a result of adduct formation at these sites. Overall functional changes to Pg were examined using silver staining and kinetic assays to examine normal protein cleavage by activator enzymes streptokinase (STK), tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA). MG-modified Pg exhibited decreased activation into plasmin (Pn), which is the active enzyme that forms via normal Pg cleavage, by all three activator enzymes. Activation into Pn by STK was significantly delayed by MG modification on plasminogen. Similar effects were observed with tPA and uPA. Efforts to identify the primary sites of MG adduction on Pg by two dimensional gel electrophoresis (2DGE) identified six sites, including R504 and R530, as the earliest modified sites. In order to probe MG site specific modification effects on lysine binding, MG-modified protein was run through a lysine-sepharose binding column and fractions were collected. The results indicated that MG-modified Pg bound more weakly to the column and eluted easier than unmodified Pg and LC-MS/MS using a LTQ Orbitrap Velos of the fraction indicated that R504 and R530 were the primary sites of MG adduction within the eluate. To assess MG-modification of Pg in humans, 12 plasma samples were immunodepleted of the top 14 abundant proteins and samples were analyzed by LC-MS/MS using a LTQ Orbitrap Velos. Nine of the 12 patient samples indicated the presence of MG-modified peptides. The antihyperglycemic drug metformin, a drug that scavenges MG and lowers formation of AGEs, was studied in order to better elucidate this scavenging mechanism. A novel reaction imidazolinone product, IMZ, was determined to be the primary product formed in the reaction between metformin and MG, confirmed unequivocally through x-ray diffraction analysis. In order to determine levels of IMZ in human patients on metformin therapy, multiple reaction monitoring (MRM) was employed to quantify the compound. Human urine samples from 92 patients on metformin treatment were analyzed. 66 of the 68 patients to exhibit high concentrations of metformin also indicated the presence of IMZ in their urine. The remaining samples either exhibited no metformin, or levels of metformin too low to detect the presence of IMZ. Importantly, IMZ was never identified in patients without a metformin signal, indicating the validity and quality of the assay. This dissertation builds upon the current knowledge of site-specific MG modifications, both in vitro, identifying for the first time Pg as a sensitive site-specific target of glycation, with functional effects, and importantly in humans, as this is the first identification of MG-modified Pg in vivo. The functional effects associated with this modification may provide a link between elevated MG in T2DM, and resulting cardiovascular complications. Additionally, the identification of the novel reaction product IMZ is important, as it helps to fully elucidate the role metformin plays in treating T2DM patients. The detection of IMZ in the urine of human patients on metformin therapy indicates that metformin plays a role in the reducing MG levels through scavenging in vivo, and the developed MRM method allows for future rapid, sensitive study of cohorts to better understand this mechanism and the role it plays in reducing AGEs and diabetic complications.

The purpose of this research was to evaluate the impact of glycemic measures, and changes in identified risk factors (BMI, waist circumference, lipids, blood pressure) on follow-up glycemia, in Pima children at high risk for type two diabetes (type 2 DM).I computed incidence and cumulative incidence of type 2 DM in Pima children 5-19 years of age between 1983 and 2004. Cox proportional hazards rates for development of type 2 DM were calculated by glycemic measure (HbA1C, 20PG, FPG) controlling for confounding factors (age, sex, BMI, blood pressure, and cholesterol). Diabetes was defined by the presence of at least one of four criteria: 1) 20PG of >200 mg/dl, 2) FPG of >126 mg/dl, 3) HbA1C > 8.0%, or 4) hypoglycemic treatment. Linear regression models were computed to identify the impact of changes in risk factors on changes in HbA1C. Only exams performed in non-diabetic children during childhood were included in the regression models.Among 2658 non-diabetic children, 258 cases of diabetes occurred during mean 9.1 years of follow-up (1.5 - 21.7). The age-sex adjusted incident rate of diabetes was 19.0 cases per 1000 person-years, and cumulative incidence was 54% by age 40. Incidence rates increased with increasing baseline values of 20PG, and FPG, but not for HbA1C. For HbA1C the relationship was u-shaped with the lowest and highest quartiles having the highest DM rates. After adjustment for confounding risk factors using Cox proportional hazards analysis, the risk for diabetes increased 2-fold for every 10 mg/dl increase in FPG. Changes in waist circumference best predicted changes in HbA1C (R2 = 0.48, Ï <0.001). However, the ability of waist circumference to predict change is limited due to the powerful effect of regression to the mean, suggesting that these risk factors contribute very little to changes in HbA1C, at least in childhood.Childhood levels of glycemia predict development of type 2 DM later in life. While changes in waist circumference are associated with only moderate changes in HbA1C, this does not refute the significant contribution of adiposity in childhood to the development of type 2 DM.

Abstract Validity of waist-to-height ratio as a screening tool for type 2 diabetes risk in non-Hispanic Whites, non-Hispanic Blacks, and Mexican American Adult Women, from the ages 20-65 years of age. Background: A prominent screening measure for type 2 diabetes is a simple measure of waist circumference. Waist circumference is an aggregate measurement of the actual amount of total and abdominal fat accumulation and is a crucial correlate of the complexities found among obese and overweight patients. However, waist circumference does not take into consideration the frame of an individual. Hence, recent epidemiologic data have suggested the use of height adjusted waist circumference (waist-to-height ratio). The use of waist-to-height ratio in screening for type 2 diabetes is poorly understood. Aims: The aim of this study is to determine racial/ethnic differences in the association of the independent variables waist-to-height ratio and waist circumference, with type 2 diabetes in non-Hispanic Whites, non-Hispanic Blacks, and Mexican American adult women, ages 20-65 years old. Methods: Data from the NHANES 2007-2008 surveys were used. Race/ethnic specific odds ratios from univariate and multivariate logistic regression models were to estimate the associations of waist-to-height ratio and waist circumference with type 2 diabetes. In the multivariate models, adjustments were made for age and alcohol use. Results: In the univariate models, WC was associated with 1.06, 1.07 and 1.04 increased odds of type 2 diabetes in Mexican Americans, non-Hispanic Whites and non-Hispanic Blacks, respectively. The corresponding values waist-to-height ratio were 2.85, 3.20 and 1.88, respectively. On adjusting for confounders, WC was associated with 1.07, 1.05, and 1.05 increased odds of type 2 diabetes in Mexican Americans, non-Hispanic Whites and non-Hispanic Blacks, respectively. WHtR was associated with 2.95, 2.38, and 2.37 increased odds of type 2 diabetes in Mexican Americans, non-Hispanic Whites and non-Hispanic Blacks, respectively. Conclusion: This study indicates that WHtR may be a powerful anthropometric predictor of risk for type 2 diabetes for Mexican American, non-Hispanic White and non-Hispanic Black American women ages 20-65.The literature on WHtR as a screening tool for type 2 diabetes in American women is lacking. This study is one of the first to examine the association between WHtR across varying races of American women. Future researchers should explore populations of women and men in the US with more races represented.

ABSTRACT Background: Prediabetes is a precursor condition to type 2 diabetes mellitus. Previous research and clinical trials have shown that the onset of type 2 diabetes could be delayed or prevented through structured life style modifications such as dietary changes, modest weight loss and moderate-intensity exercise. This study examines U.S adults of different ethnicities that include non-Hispanic white, non-Hispanic black and Mexican Americans and whether their awareness of diabetes risk is associated with their participation in diabetes risk reduction behavior, a combination of physical activity, weight control and fat/calories intake. Methods: The 2007-2008 National Health and Nutrition Examination Survey, NHANES, was used to conduct a cross-sectional study of 4083 U.S. adults who were 20 years old and above and were aware of their diabetes risk. The association between the awareness of one’s diabetes risk and the adoption of diabetes risk reduction behavior were examined in present of other risk factors such as age, gender, ethnicity, education, annual family income, BMI, hypertension, mean systolic blood pressure, mean diastolic blood pressure, total cholesterol, LDL, HDL and triglyceride levels. Males and females were examined separately for all analyses performed. Cross tabulation was conducted and p-values were calculated by the Pearson’s chi-square test for the categorical variables which include gender, ethnicity, education, annual family income, adiposity and hypertension. One Way ANOVA and Tukey post hoc tests were conducted for the continuous variables which include age, mean systolic blood pressure, mean diastolic blood pressure, total cholesterol, LDL, HDL and triglyceride levels. Univariate and multivariate analyses were performed to determine the association between the main independent variable, awareness of one’s diabetes risk, and the dependent variable, adoption of diabetes risk reduction behavior, controlling for other risk factors. A p-value of <0.05 and 95% confidence intervals were used to determine statistical significance throughout all analyses performed. Results: After controlling for age, gender, race, education, annual family income, BMI, hypertension, mean systolic blood pressure, mean diastolic blood pressure, total cholesterol, LDL, HDL, and triglycerides, results from the multivariate analysis showed that subjects who were aware of their diabetes risk were more likely to adopt diabetes risk reduction behavior (OR= 1,734, 95 % CI=1.217-2.470). Females and non-Hispanic blacks, who were aware of their diabetes risk, were also more likely to adopt diabetes risk reduction behavior compared to males, non-Hispanic whites and Mexican Americans. An increase in the levels of education, annual family income and BMI was also associated with the adoption of diabetes risk reduction behavior. Stratification according to gender and ethnicity, showed that Mexican American males and females were more likely to engage in diabetes risk reduction behavior compared to non-Hispanic whites and non-Hispanic blacks (Mexican American males: OR: 2.496, CI: 0.792-7.868; Mexican American females: OR: 2.830, CI: 0.917-8.736). Conclusion: This study provides useful insights for health care providers and public health professionals who are developing health promotion and prevention interventions to address pre diabetes before it develops into type 2 diabetes. This study also allows the development of tailored interventions for specific genders and ethnic groups that are at risk. Results of this study indicate that Mexican Americans and females (in general) are more likely to adopt diabetes risk reduction behavior. Therefore, physicians and health care providers should develop culturally, linguistically and gender- specific education materials and programs for this particular gender and ethnic group. This in turn, may reduce the overall increasing prevalence of diabetes, reduce racial and gender disparities and may have a positive impact on the overall health of the U.S. population.