Objectives To evaluate the effectiveness of pharmacist-physician collaboration in the treatment of type 2 diabetes mellitus (DM) with severe insulin resistance, using 500 U/mL concentrated regular insulin (U-500) in a primary care clinic that is not staffed by an endocrinologist. Methods A retrospective chart review was conducted searching for patients who were prescribed U-500 insulin from January 1, 2008 through December 31, 2014. Subjects were included in the analysis if the pharmacist initiated U-500 insulin therapy, received treatment for at least 6 months, and who attended at least one follow-up visit with the pharmacist. Anyone who received U-500 insulin before the initial pharmacist consultation, managed by an endocrinologist, or who was missing follow-up hemoglobin A1c (HbA1c) laboratory values during the follow-up period was excluded. The primary endpoint was the change in HbA1c from U-500 initiation to 6 months later. Secondary endpoints included changes in weight, confirmed hypoglycemia events, changes in other anti-DM medications and the number of pharmacist and primary care physician visits during the follow-up period. Results Eighty-one patients were identified and screened, and 44 patients were included in the analysis. Baseline HbA1c (mean ± standard deviation) was 9.7% ± 1.6% and decreased to 8.6% ± 1.6% after 6 months of follow-up, representing a reduction of 1.1% (95% confidence interval -1.6 to -0.6, P < 0.001). Body weight increased (mean ± standard deviation) by 6.7 ± 15.1 lb from baseline (P = 0.005). The frequency of confirmed hypoglycemia events was low (0.8 events per patient). Treatment with metformin was preserved, whereas most other DM medications were discontinued. A similar number of pharmacist and physician follow-up visits were completed by the end of the study period (2.0 and 2.7 visits, respectively; P = 0.805). Conclusions Initiation of U-500 insulin by clinical pharmacists collaborating with primary care physicians results in improved DM control in patients with severe insulin resistance. Our findings suggest this interprofessional partnership provides an alternative referral approach for primary care physicians when endocrinology services are absent or limited.

The human forkhead box O1A (FOXO1A) gene on chromosome 13q14.1 is a key transcription factor in insulin signaling in liver and adipose tissue and plays a central role in the regulation of key pancreatic β-cell genes including IPF1. We hypothesized that sequence variants of FOXO1A contribute to the observed defects in hepatic and peripheral insulin action and altered β-cell compensation that characterize type 2 diabetes (T2DM). To test this hypothesis, we screened the three exons, 3′ untranslated region, and 5′ flanking region for sequence variants in Caucasian and African-American individuals with early onset (<45 years) T2DM. We identified only six variants; none altered the coding sequence, and except for one variant in the 3′ untranslated region, they were rare or absent in Caucasians. To increase coverage of the gene, we selected seven additional variants in the large first intron and 5′ flanking region, thus providing 13 variants that spanned 116.4 kb. Based on frequency and linkage disequilibrium patterns in a subset of individuals, we selected eight SNPs to type in a Caucasian population comprising 192 unrelated nondiabetic control individuals and 192 individuals with T2DM, and 10 SNPs to type in 182 controls and 352 diabetic individuals of African-American ancestry. No variant was associated with T2DM (African-Americans, p > 0.08; Caucasians, p > 0.09). Of the 8 Caucasian SNPs, six comprised a single haplotype block spanning over 100 kb and including most of the large first intron. In contrast, no block was observed among SNPs typed in African-Americans. No haplotype was associated with T2DM. FOXO1A variation is rare and is unlikely to contribute to T2DM in either Caucasian or African-American populations.

Background: One-third of the U.S. population has prediabetes, but 90% remain undiagnosed because healthcare providers are not screening for this condition. Objective: The purpose of this quality improvement project was to monitor prediabetes screening and identification, and implement evidence-based recommendations including registered dietician referral. Methods: This project involved using an evidence-based screening tool to measure individual risk of prediabetes. Aggregate data was collected to evaluate screening implementation, evidence-based recommendations offered by providers, and assess patient risk factors. Results: The percentage of patients at risk for prediabetes was 41.3% (n = 111). The most frequent risks were identified as overweight, history of hypertension, family history of type 2 diabetes mellitus (T2DM), and older age. Providers offered education on weight loss 68.5% (n = 76) and exercise 76.6% (n = 85) but referred 33.3% (n = 37) patients for nutrition education. The screening rates were 52.3% (n = 176) and 72.5% (n = 244) in clinics A and B respectively. Conclusions: A gap remains in using evidence-based recommendations to decrease risk of prediabetes. Prediabetes screening identified a greater percentage of persons in this population. Implications for Nursing: There is a need for consistent practice of evidence-based recommendations. This project set the benchmark for future efforts to educate, encourage, and measure providers successes.

Ammonia is a toxic by-product of protein catabolism and is involved in changes in glutamate metabolism. Therefore, ammonia metabolism genes may link a range of diseases involving glutamate signaling such as Alzheimer’s disease (AD), major depressive disorder (MDD), and type 2 diabetes (T2D). We analyzed data from a National Institute on Aging study with a family-based design to determine if 45 single nucleotide polymorphisms (SNPs) in glutaminase (GLS), carbamoyl phosphate synthetase 1 (CPS1), or glutamate-ammonia ligase (GLUL) genes were associated with AD, MDD, or T2D using PLINK software. HAPLOVIEW software was used to calculate linkage disequilibrium measures for the SNPs. Next, we analyzed the associated variations for potential effects on transcriptional control sites to identify possible functional effects of the SNPs. Of the SNPs that passed the quality control tests, four SNPs in the GLS gene were significantly associated with AD, two SNPs in the GLS gene were associated with T2D, and one SNP in the GLUL gene and three SNPs in the CPS1 gene were associated with MDD before Bonferroni correction. The in silico bioinformatic analysis suggested probable functional roles for six associated SNPs. Glutamate signaling pathways have been implicated in all these diseases, and other studies have detected similar brain pathologies such as cortical thinning in AD, MDD, and T2D. Taken together, these data potentially link GLS with AD, GLS with T2D, and CPS1 and GLUL with MDD and stimulate the generation of testable hypotheses that may help explain the molecular basis of pathologies shared by these disorders.

Background The pleckstrin and Sec7 domain-containing 3 (PSD3) gene has been linked to immune diseases. We examined whether the genetic variants within the PSD3 gene are associated with obesity, type 2 diabetes (T2D), and high-density lipoprotein (HDL) cholesterol level. Methods Multiple logistic regression model and linear regression model were used to examine the associations of 259 single nucleotide polymorphisms (SNPs) within the PSD3 gene with obesity and T2D as binary traits, and HDL level as a continuous trait using the Marshfield data, respectively. A replication study of obesity was conducted using the Health Aging and Body Composition (Health ABC) sample. Results 23 SNPs were associated with obesity (p < 0.05) in the Marshfield sample and rs4921966 revealed the strongest association (p = 3.97 × 10−6). Of the 23 SNPs, 20 were significantly associated with obesity in the meta-analysis of two samples (p < 0.05). Furthermore, 6 SNPs revealed associations with T2D in the Marshfield data (top SNP rs12156368 with p = 3.05 × 10−3); while two SNPs (rs6983992 and rs7843239) were associated with both obesity and T2D (p = 0.0188 and 0.023 for obesity and p = 8.47 × 10−3 and 0.0128 for T2D, respectively). Furthermore, 11 SNPs revealed associations with HDL level (top SNP rs13254772 with p = 2.79 × 10−3) in the Marshfield data; meanwhile rs7009615 was associated with both T2D (p = 0.038) and HDL level (p = 4.44 × 10−3). In addition, haplotype analyses further supported the results of single SNP analysis. Conclusions Common variants in PSD3 were associated with obesity, T2D and HDL level. These findings add important new insights into the pathogenesis of obesity, T2D and HDL cholesterol.

Aims The associations of moderate alcohol consumption, sleep duration, and tobacco smoking with coronary heart disease (CHD) among patients with type 2 diabetes mellitus (T2D) are not clearly clarified. The aims of the study were to evaluate the associations of lifestyle factors, hypertension, obesity, depression and sleep duration with CHD development among patients with T2D, and particularly, to examine the gender differences in risk factors for CHD. Methods A total of 2335 T2D adults were selected from the 2012 National Health Interview Survey. Weighted univariate and multiple logistic regression analyses were used to estimate the odds ratios with 95% confidence intervals. Results The CHD prevalence among patients with T2D was 14.2% (18.1% and 10.4% for males and females, respectively), which increased with age (10.3% and 19.6% for age groups 18–64 and 65+, respectively). After adjusting for other factors, weighted logistic regression analyses showed that CHD among patients with T2D was significantly associated with being male, older age, past smoking, long sleep duration, hypertension, and high cholesterol level. Furthermore, the significant association of older age, past smoking, hypertension and high cholesterol level were observed particularly in males, while the association of long sleep duration with CHD was only observed in females. Hypertension was associated with CHD for both genders. Conclusions Gender, age, past smoking, long sleep duration, hypertension and high cholesterol level were significantly associated with CHD among T2D patients; however, such associations differed by gender. Such gender disparities should be considered in the prevention and treatment of T2D.

Skeletal muscle insulin resistance is a major characteristic of obesity and type 2 diabetes. Although obesity-mediated inflammation is causally associated with insulin resistance, the underlying mechanism is unclear. Our lab and others have shown that a chronic low-grade inflammation takes place in skeletal muscles during diet-induced obesity, as evidenced by increased macrophage markers and pro-inflammatory cytokine levels. Interleukin (IL)-10 is a Th2-type cytokine that inhibits the synthesis and activity of pro-inflammatory cytokines and counteracts the Toll-like receptor-mediated inflammation. Our lab has previously demonstrated the preventive role of IL-10 against insulin resistance. Here, I have analyzed the effects of IL-10 on the skeletal muscle glucose metabolism and myogenesis in three different insulin resistant states (high fat diet-induced, leptin-deficiency-induced and aging-induced). The first model involved long-term (16 weeks) high-fat diet (HFD) feeding that resulted in markedly obese and hyperglycemic mice, representative of obese type 2 diabetic subjects. In mice overexpressing IL-10 specifically in the skeletal muscle (MIL10), we observed improved whole-body and skeletal muscle insulin sensitivity as compared to wild-types after long-term high fat diet feeding. The improved insulin sensitivity in the skeletal muscle was due to increased Akt signaling and decreased muscle inflammation. Leptin is an important adipocyte-derived hormone that is elevated in obesity, and it regulates numerous physiological functions including the energy balance and inflammation. Thus, my second model examined the effects of muscle-specific overexpression of IL-10 on glucose metabolism in the hyperphagic, leptin-deficient ob/ob mice. We detected improved whole-body insulin sensitivity compared to the control mice. My third model examined the effects of increased IL-10 expression using MIL10 mice during aging-induced insulin resistance. In 18-month old MIL10 mice, we found enhanced whole-body and skeletal muscle insulin sensitivity due to improved insulin signaling and decreased muscle inflammation as compared to wild-type mice. Last, to test whether direct signaling of IL-10 on skeletal muscle is responsible for the beneficial effects of IL-10 on muscle glucose metabolism, I generated mice lacking IL-10 receptor 1 type chain selectively in skeletal muscle (M-IL10R-/-). We observed more prominent muscle inflammation and whole-body insulin resistance in HFD-fed M-IL10R-/- mice as compared to wild-type mice. Interestingly, when studying insulin resistance in the IL-10 transgenic mouse models, we identified a consistent increased lean mass phenotype, and conversely decreased lean mass in the HFD-fed M-IL10R-/- mice. Quantitative RT-PCR on HFD-fed MIL10 group muscles to measure myogenesis-related gene expression identified a correlation between lean mass and both IL-10 and MyoD mRNA expression levels. In support of this, I showed that IL-10 caused an increase in in vitro cultured myoblast proliferation rates. Together, these results highlight the potential benefits of IL-10 expression not only in muscle glucose metabolism but also in maintaining muscle mass during insulin resistant states. Overall, these results demonstrate that selective expression of IL-10 in skeletal muscle suppresses inflammation, improves glucose metabolism and muscle growth in obese and aging mice, and further establishes that these effects are at least partially mediated by direct activation of IL-10 signaling in skeletal muscle.

BACKGROUND In 2010, glycated haemoglobin A1c (HbA1c) was officially recommended as a screening tool to diagnose type 2 diabetes mellitus (T2DM) and pre-diabetes, with cut-off points 6.5% and 5.7% to 6.4% respectively. The implications of using the HbA1c criterion, compared to the general diagnostic criteria: fasting glucose test (FPG) and oral glucose tolerance test (OGTT), is however still being debated. OBJECTIVES The objectives of this study were to evaluate and compare the pooled prevalence of type 2 diabetes mellitus (T2DM) and pre-diabetes, as measured by the Haemoglobin A1c (HbA1c) test, or the fasting plasma glucose (FPG) and oral glucose tolerance test (OGTT). Secondly, to determine and compare the diagnostic test characteristics (sensitivity, specificity) of these tests. METHODS Published papers, with a cross sectional study design, were selected for a systematic review and meta-analysis. The search strategy was an electronic review of journal articles listed on MEDLINE, PubMed and Google scholar between 1996 and 2012. Reference lists were checked, journals were hand searched and experts were contacted when necessary. Initially all studies related to the validation of HbA1c as a tool to detect pre-diabetes or T2DM in humans, published in English, were examined. Studies were excluded if they did not meet the above mentioned criteria, and/or were conducted with pregnant women. Further analysis was done if FPG or OGTT was compared to HbA1c. The diagnosis of diabetes had to have been based on ADA or WHO criteria. These criteria are: HbA1c 5.7%-6.4% for pre-diabetes and >=6.5% for T2DM; FPG 5.6mmol-7mmol/l for pre-diabetes and >=7mmol/l for T2DM; OGTT 7.8mmol-11.1mmol/l for pre-diabetes and >=11.1mmol/l for T2DM). The OGTT and FPG tests were used as the reference tests and the prevalence reflected as a positive or negative proportion. The sensitivity and specificity of HbA1c >=6.5% among cases defined by OGTT or FPG should have been reported, or it was possible to calculate these from the data provided. Study results relating to diagnostic accuracy were extracted and synthesized using multivariate random effects meta-analysis methods. This study focused on patients who were suspected of having T2DM, from two sub-groups (a community-based group and a high-risk group) to compare the detection rate of HbA1c with FPG and OGTT. / Dissertation (MSc)--University of Pretoria, 2014. / lk2014 / School of Health Systems and Public Health (SHSPH) / MSc / Unrestricted

Both plasma glucose concentration and glucose uptake are deranged in insulin resistance. A high free fatty acid plasma level is a potential cause of insulin resistance, and therefore of type 2 diabetes mellitus animals and humans. The mechanism behind this is still unclear. The objectives of the present study were: (i) to research the effect of arachidonic acid (AA) as fatty acid representative, on glucose uptake into human isolated adipocytes, (ii) to investigate the uptake of AA into adipocyte membranes and nuclei, as a step to identify the mechanism whereby AA affects glucose uptake, and (iii) to verify the influence of insulin on AA uptake in adipocytes. The first objective was achieved by exposing adipocytes to AA and measuring the effect on deoxyglucose uptakt. To achieve the second objective, adipocytes were exposed to 14C-AA; radioactive uptake in membranes and nuclei was determined. The AA uptake into membranes was also determinate by membranes fatty acid profile using gas chromatography; the results of the two methods were compared. Finally, the third objective was achieved by exposing adipocytes to different concentrations of insulin and testing the effect by measuring arachidonic acid uptake by the entire cell. The results of this study shown that, acute (30 min) exposure of AA significantly stimulates glucose uptake by adipocytes (4.56 ± 0.6 nmole glucose /mg protein /min) compared to the control (3.12 ± 0.25 nmole glucose /mg protein /min). Secondly, 14C-AA was significantly taken up by the membranes between 20 and 30 minutes of exposure. The uptake into membranes was increased by 49.57 ± 29% and 123 ± 73% compared to the control 100% (1.77 ± 0.06 nmole AA /mg protein) respectively for 20 and 30 min exposure). AA significantly rose in the nuclei after 30 minutes (147 ± 19% increase) compared to the control 100% (2.25 ± 0.10 nmole AA /mg protein). The determination of AA uptake by gas chromatography analysis of the membrane fatty acid profile showed that the content of AA increased after 30 min exposure (0.57% AA of total membrane fatty acids) compared to the 10 min exposure (0.29% AA of total membrane fatty acid). Insulin was shown to stimulate 10 and 30 min AA uptake by adipocytes from a non-obese subject. The increases of AA uptake measured for 30 minutes were 20 ±8%, 21 ± 25% and 31 ± 4% compared to the control (0.58nmole AA / mg protein / min) respectively for the actions of 10nM, 20nM and 40 nM insulin. A similar tendency was observed when the AA uptake was measured for 10 min (81 ± 31% and 208 ± 36% respectively for the action of 10nM and 40nM insulin compared to the control 100% (0.06nmole AA/mg protein/min). In contrast to this finding, insulin depressed AA uptake by adipocytes from an obese subject (depression of 15 ± 5%, 14 ± 8% and 21 ± 5% respectively for 10nM, 20nM and 40nM insulin, compared to the control 100% (0.74 nmole AA/mg protein/min). In both situations the effect of insulin seemed dose dependent. The study demonstrated that AA acid positively modulates glucose uptake into adipocytes exposed for short periods (< 30 min). This was attributed to the probable this FA in the cell membrane, rather than its eventual effect on the DNA. The best method to measure membranes AA over short period of exposure when small amounts of adipocytes (2- 6 ml) are used was by radioactive means. It also suggested that insulin effect’s on AA acid uptake into adipocytes was dose dependent. This varies with the body mass index (BMI) of the patient, probably as a result of their cell’s insulin resistant state. / Dissertation (MSc (Veterinary Science))--University of Pretoria, 2007. / Anatomy and Physiology / MSc / unrestricted

Background: India's growing economy has led to radical lifestyle changes and one of the consequences is an unexpected explosion of non-communicable diseases, such as Type 2 Diabetes. The prevalence of Type 2 Diabetes has more than doubled since 1980 from four to over eight percent in 2016. India has today the second largest adult population affected by Type 2 Diabetes in the world. 72.9 million adults had diabetes in India 2017 and by year 2035 this number is predicted to rise to 109 million. To cope with this epidemic, patients will need to perform adequate self-management. Nurses’ may have a major part in providing the support and knowledge patients require to be able to perform this.  Aim: The aim of the study is to describe nurses’ experience of good self-management among patients diagnosed with T2D. Method: The study has a descriptive and qualitative design. Semi structured interviews with open-ended questions were carried out at a hospital setting in Kerala, India. Results: The analysis from the interviews resulted in three sub-themes and one main theme. The three sub-themes are Support from the family is fundamental for the patient's well-being, The importance of individualized care and The importance of teaching patients how to manage their condition. The three sub-themes resulted in the main theme Three Cornerstones for good self-management. Discussion: The result demonstrates that the nurses’ finds individualized care as an important matter. The participants declare that patients have different knowledge regarding Type 2 Diabetes, and how individualized care is a way to provide what the patient requires in order to perform self-management. The nurses also express how they always involve the patients' family, since their experience is that the absence of the family impairs the patient's condition.