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The prevalence of insulin resistance and type 2 diabetes mellitus (T2DM) in obese children and adolescents is growing at an alarming rate, especially in ethnic minorities. It is not clear whether young people of different ethnic backgrounds vary in their metabolic response to excessive adiposity. Differences in lipid partitioning in the abdominal fat compartments have been observed among different ethnic groups. The aim of this study was to evaluate whether there are ethnic differences in intramyocellular lipid (IMCL) levels that are related to differences in insulin sensitivity. Eighty-two obese children and adolescents underwent 1) 1H nuclear magnetic resonance (NMR) spectroscopy to non-invasively quantify IMCL levels in their soleus muscle, 2) an oral glucose tolerance test and (in a subset of subjects) a euglycemic-hyperinsulinemic clamp to assess insulin sensitivity, 3) a dual-energy X-ray absorptiometry (DEXA) scan to measure total percent body fat, and 4) magnetic resonance imaging to measure abdominal fat distribution. IMCL levels in Hispanic children and adolescents (1.50 ± 0.64%) were significantly greater than in their Caucasian (1.19 ± 0.40%) and African-American (1.09 ± 0.49%) peers. Visceral fat was significantly lower in African Americans (42.7 ± 18.8cm2) and were similar in Caucasians (70.9 ± 27.5cm2) and Hispanics (77.3 ± 41.9cm2). The three groups were not different with respect to insulin sensitivity. For the entire cohort, IMCL levels were inversely related to insulin sensitivity. There was a significant correlation between visceral fat and insulin resistance in Hispanics and Caucasians but not in African Americans. In conclusion, these data suggest that there are significant ethnic differences in lipid partitioning in both the muscle and abdominal compartment. These findings may explain ethnic differences in insulin sensitivity and further the understanding of the pathogenesis of insulin resistance and T2DM.

Thesis (M.A.)--Indiana University, 2009. / Title from screen (viewed on February 1, 2010). Department of English, Indiana University-Purdue University Indianapolis (IUPUI). Advisor(s): Ulla M. Connor, Frank M. Smith, Honnor Orlando. Includes vitae. Includes bibliographical references (leaves 138-139).

Abstrakt Bakgrund: Typ 2 diabetes är en livsstilssjukdom som ökar både i Sverige och globalt. Egenvården är en viktig del i behandlingen av sjukdomen och är en livslång uppgift. Sjuksköterskan har en viktig roll i att, genom stöd, undervisning och vägledning, motivera och stärka personens egenvårdskapacitet. För att bättre förstå personens behov i egenvården är det betydelsefullt att sjuksköterskan får ta del av personers erfarenheter av egenvård vid typ 2 diabetes. Syfte: Syftet med denna litteraturstudie var att belysa personers erfarenheter av egenvård vid typ 2 diabetes. Metod: Litteraturstudie baserad på tolv kvalitativa artiklar. Artiklarna söktes i databaserna Cinahl och PubMed. Artiklarna kvalitetsgranskades och analyserades och kategorier och underkategorier identifierades.  Resultat: Resultatet kategoriserades i fyra kategorier och elva underkategorier. Dagligt liv med underkategorier kost, fysisk aktivitet, läkemedelsbehandling och blodsockerkontroll. Stöd; socialt stöd, stöd i samband med sociala sammankomster, familjen som stöd och tron som stöd. Psykiska aspekter; motivationens betydelse för egenvård och känslor i samband med egenvård. Kunskap/information; kunskap och förståelse och behov av diabetesutbildning. Konklusion: Erfarenheter av egenvård varierar från person till person. Att kunna stödja och motivera personen till egenvård ställer stora krav på sjuksköterskans omvårdnadskapacitet. Mycket talar för att Orems egenvårdsteori är användbar i sjuksköterskans arbete med detta.  Nyckelord: Typ 2 diabetes, egenvård, Orem, patientperspektiv, omvårdnad.

PANcreatic-DERived Factor (PANDER), or FAM3B, is a 235-amino acid protein strongly expressed within and secreted from the endocrine pancreas. Research surrounding PANDER has revealed a large role for the protein in maintaining glucose homeostasis, as evidenced by several Ad-PANDER overexpressing murine models, our lab's pancreas-specific PANDER transgenic overexpressor, and most recently our mixed genetic C57/129J PANDER knockout (PANKO) mouse. However, PANDER's overall role in glycemic regulation and glucose homeostasis has yet to be studied in a purebred C57BL/6J PANDER knockout model. Here we present the first phenotypic characterization of our global PANDER knockout mouse on a C57BL/6J background (PANKO-C57) where we examined metabolics through glucose/insulin tolerance testing, fasting glycemia, and body weights, the concentrations of hormonal analytes along with lipids and corticosterones, and full elucidation of hepatic insulin signaling through the insulin signaling cascade. Overall, the PANKO-C57 mice exhibited increased body weights with enhanced glucose tolerance and lower fasting glycemia, similar peripheral insulin sensitivities, increased hepatic lipidemia, and enhanced hepatic insulin signaling at critical insulin signaling molecules. Taken together, the PANKO-C57 demonstrates that the disruption of PANDER results in selectively enhanced hepatic insulin signaling yet with increased lipidemia and overall body weight. These findings reveal a novel role for PANDER in differentially controlling lipogenesis and hepatic glucose production that may selectively impact overall glycemic control and potentially facilitate the onset and/or progression of type 2 diabetes.

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).