The present study assessed the relationship between Body Mass Index (BMI) and healthcare cost, utilization and health-related quality of life (HRQoL) of type 2 diabetes patients using the Medical Expenditure Panel Survey (MEPS) database. Study subjects were at least 18 years of age, diagnosed with diabetes and taking ≥1 oral antidiabetic medication. Data were extracted over a 5-year period (01/01/2006-12/31/2010). The main study outcomes were healthcare costs and utilization and HRQoL. The study covariates were age, gender, race, smoking status, census region of residence, marital status, insurance status, Charlson comorbidity index score and additional bed days. Study objectives were addressed using generalized linear model, negative binomial and multivariate regression analyses. A final un-weighted sample size of 7,003 patients was obtained. Mean age (±SE) was 61.2 (±0.24) years, mean BMI (±SE) was 32.2 (±0.12), and 50.4% were males. The majority was white (77.4%), did not smoke (84.5%), and were married (60.4%). Based on BMI categories, 12.6% had normal weight (BMI: 18.0-24.9); 29.2% were overweight (BMI: 25.0-29.9); 45.6% were obese (BMI: 30.0-39.9), and 12.6% were morbidly obese (BMI≥ 40.0). Compared to normal-weight patients; overweight, obese or morbidly obese patients had significantly higher (p<0.05) diabetes-related direct medical costs. However, overweight patients had significantly lower (p=0.021) all-cause direct medical costs. Furthermore, compared to normal weight patients, obese patients had a significantly higher (p=0.009) number of ambulatory care visits, while overweight patients had a significantly lower (p=0.035) number of emergency department visits. In addition, being obese or morbidly obese was associated with a significantly higher (p<0.0001) number of prescribed medicines compared to normal-weight patients. Compared to normal-weight patients; being obese or morbidly obese was also significantly (p<0.0001) associated with lower physical component summary (PCS-12) scores (i.e., worse quality of life) while being overweight was significantly (p=0.038) associated with higher mental component summary (MCS-12) scores (i.e., better quality of life). In conclusion, the present study suggests that among type 2 diabetes patients, being obese may be associated with negative consequences (in terms of healthcare costs, utilization and outcomes). Hence, there is the need to address obesity among type 2 diabetes patients in order to improve their health outcomes and significantly reduce healthcare costs and resource utilization. / text

This thesis used attachment theory and the common sense model of illness as theoretical backgrounds to examine the mechanisms that contribute to the quality of the support seeking behaviour and social interactions between patients with type 2 diabetes and their partners. Specifically, this thesis examined actor and spouse effects of working models of attachment on health outcomes, and illness perceptions on health outcomes for both patients and partners. Furthermore, it determined if support seeking, supportive interactions, and negative interactions mediated between the attachment and health outcomes and illness perception and health outcomes. At study entry, 70 patients with type 2 diabetes and their partners completed measures on attachment, illness perceptions, support seeking, receipt of supportive interactions and of negative interactions, satisfaction with support received, and health outcomes. Health outcomes included psychological distress and physical health for patients and partners, and diabetes well-being for patients only. Six months later, participants again completed measures on supportive and negative interactions, satisfaction with support received, and health outcomes. The data were examined both cross-sectionally (including mediational analyses) and longitudinally. The cross-sectional analyses revealed a number of actor and spouse effects in the relationships between attachment and health outcomes, and illness perceptions and health outcomes. Patients who scored higher on attachment-anxiety experienced higher levels of psychological distress and lower levels of diabetes well-being. Also, the partners of these patients experienced higher levels of psychological well-being. Furthermore, covert support seeking behaviour and negative interactions were found to be significant mediators between patient attachment-anxiety and patient psychological distress and diabetes well-being. In addition, support satisfaction mediated the relationship between patient attachment-anxiety and patient psychological distress. Illness perceptions, specifically timeline cyclical perceptions, were also shown to be related to health outcomes, and receipt of negative interactions. Patients and partners who scored higher on timeline cyclical experienced higher levels of psychological distress. Also receipt of negative interactions mediated the relationship between timeline cyclical and psychological distress. Some significant changes over time found when the data were examined longitudinally. For example, patients who scored higher on attachment-anxiety at study entry experienced higher levels of psychological distress over time, and had a partner who also experienced higher levels of psychological distress over time. In addition, partners who scored higher on personal control and who had a spouse (patient) who scored higher on timeline cyclical at study entry experienced higher levels of psychological distress overt time. Taken together, both the cross-sectional and longitudinal findings emphasize the contribution of the partner and his or her interactions with the patient to patient well-being. In the same manner, the results also highlight the effect of the patient’s illness on the partner’s well-being. These findings have important practical implications, especially for practitioners who aim to design intervention to help patients and their partners better adapt to the patient’s illness.

Cognition and Self-Management in Type 2 diabetes in the older person was studied using neuropsychological evaluation and self-management assessments. Type 2 diabetes is increasing in prevalence, erodes quality of life, and places significant burden on healthcare services. The condition is largely self-managed, requiring daily performance of a variety of tasks. Impaired cognition has been associated with Type 2 diabetes, particularly in those who have had diabetes for longer or are older. It is unknown whether such changes in cognition seen in Type 2 diabetes affect the ability to self-manage the condition; the few studies that have been conducted in this area have shown little consensus in focus, methodology, or results. This thesis aimed to investigate any links between cognitive impairment and diabetes self management skills in an older population with Type 2 diabetes, by determining assessment schedules for both selfmanagement and cognition in this population and searching for associations between the two. Literature review, questionnaire and focus group studies pointed towards four main components of diabetes selfmanagement; diabetes knowledge, self-efficacy, motivation, and diabetesspecific problem solving abilities. A theoretical framework emerged from this analysis; Bandura’s Social Cognitive Theory provides a context for the interaction of environment, society and cognitions in health behaviours. A systematic review found several associations between self-management skills and abilities, and global and individual areas of cognition, including links between executive function and memory, and diabetes knowledge, insulin skills, adherence to medications, missed appointments, and decreased frequency of self-care activities. A further clinical study identified several associations including visual and working memory, and reaction times, with diabetes knowledge. Future studies with larger sample sizes might revisit these associations. Clinical implications include the need for routine cognitive assessment in an older population with Type 2 diabetes; interventions might include checking medication adherence, diabetes knowledge, and referral to support groups.

The prevalence of obesity and type 2 diabetes has increased at alarming rates in recent decades. These diseases are prominent components of the metabolic syndrome, which is characterized by marked dyslipidemia. Adipose tissue contributes to the development of obesity-related diabetes through increased release of hormones and non-esterified fatty acids. The development of sensitive analytical tools for the broad detection of lipid biomolecules, such as liquid chromatographymass spectrometry (LC-MS), has spurred interest in the molecular determinants of the metabolic syndrome. The development of mature adipocytes from precursor fibroblasts—adipogenesis—plays a crucial role in the expansion of adipose tissue in obesity. We profiled differentiating 3T3-L1 pre-adipocytes by LC-MS and found that a class of monoglyceride lipids, monoalkylglycerol ethers (MAGEs), was transiently elevated early in adipogenesis. Upon addition to differentiating cells, MAGE specifically promoted adipocyte maturation and expression of adipogenic gene markers, indicating that MAGEs may be signaling molecules during adipogenesis. The insulin-sensitive glucose transporter, GLUT4, is downregulated during obesity and diabetes. In collaboration with Prof. Barbara Kahn, we studied a transgenic mouse model that overexpressed GLUT4 specifically in adipose tissue (AG4OX) and was protected from developing diabetes. We used LC-MS-based metabolomics to discover a previously undescribed class of bioactive lipids that was highly upregulated in AG4OX adipose tissue. We structurally characterized these lipids as fatty acyl hydroxy fatty acids (FAHFAs) and several positional isomers were chemically synthesized to confirm structural assignments via coelution studies. We discovered that individual FAHFAs, such as 5-palmitoyl-hydroxystearic acid (5-PAHSA), were differentially regulated by the transcription factor ChREBP. Circulating 5-PAHSA levels in mice and humans correlated with ChREBP expression and insulin resistance. In order to explore the biochemical regulation of FAHFAs, we developed an LCMS-based assay to measure FAHFA hydrolysis activity. We identified one enzyme, carboxyl ester lipase (CEL), as the major FAHFA hydrolase in pancreas, where the activity was highest. We confirmed its relevance in vivo by feeding labeled FAHFA to CEL inhibitor-treated mice. In this work we used LC-MS-based metabolomics to discover two lipids, MAGE and FAHFA, along with the CEL pathway, that may help us to better understand the pathogenesis of obesity and diabetes. / Chemistry and Chemical Biology

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

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.