Objective: Pedometer programs are effective in increasing physical activity in sedentary individuals, a population that is at an increased for developing metabolic syndrome and each of its individual components. The aim of this study was to observe the effects of incremental increases in pedometer assessed physical activity on MetS components in sedentary overweight women. Design: This study was a longitudinal, quasi-experimental design. Participants were recruited from a 12-week work-site pedometer program and grouped after the intervention based on their self-paced increases in pedometer assessed physical activity with (a) active participants that increased their daily activity by mean volume >3000 steps/day or (b) participants who remained sedentary. Subjects: A multi-ethnic heterogeneous sample of seventy-seven sedentary middle-aged women (BMI: 30.15 plus or minus 5.24 kg/m2, age: 46.00 plus or minus 9.93 years). Measurements: Self-reported physical activity, pedometer assessed physical activity (steps/day), body mass index, resting heart rate, waist circumference, blood pressure, triglycerides, HDL-C and fasting glucose at baseline and after the 12-week program. Results: The active group showed significant within-group improvements (P less than or equal to .01) in waist circumference and fasting glucose. Significant between group changes were observed in resting heart rate (P less than or equal to .01), weight (P less than or equal to .01), BMI (P less than or equal to .01), and systolic blood pressure (P less than or equal to .001); however, the changes observed in systolic blood pressure were not independent of weight loss. Conclusions: Our study showed that incremental increases in steps/day over 12 weeks is effective in inducing mild, but favorable changes in some MetS components. This data suggests that this approach to increasing step/day is a viable starting point for sedentary individuals that may find it difficult to initially accumulate 10,000 steps/day.

No description available.

abstract: Objectives: To investigate the potential of vinegar supplementation as a means for reducing visceral fat in healthy overweight and obese adults, and to evaluate its effects on fasting blood glucose and fasting insulin. Subjects and Methods: Forty-five sedentary overweight and obese adult participants with a waist circumference greater than 32 inches for women and 37 inches for men were randomly assigned to one of two groups, the vinegar group (VIN, n=21) or the control group (CON, n=24), and instructed to consume either two tablespoons of liquid red wine vinegar (3.6g acetic acid) or a control pill (0.0225g acetic acid) twice daily at the beginning of a meal for 8 weeks. Participants were also instructed to maintain normal diet and physical activity levels. Anthropometric measures, dual-energy x-ray absorptiometry (DXA) scans, blood samples, and 24-hour dietary recalls were collected at baseline and at end of trial. A compliance calendar was provided for daily tracking of vinegar supplementation. Results: Compliance to vinegar supplementation averaged 92.7 ±13.3% among the VIN group and 89.1 ±18.9% among the CON group. There were no statistically significant differences in anthropometric measurements between baseline and week 8: weight (P=0.694), BMI (P=0.879), and waist circumference (P=0.871). Similarly, DXA scan data did not show significant changes in visceral fat (P=0.339) or total fat (P=0.294) between baseline and week 8. The VIN group had significant reductions in fasting glucose (P=0.003), fasting insulin (P <0.001), and homeostatic model assessment of insulin resistance scores (P <0.001) after treatment. Conclusions: These data do not support the findings from previous studies that indicated a link between vinegar supplementation and increased fat metabolism, specifically visceral fat reduction. / Dissertation/Thesis / Masters Thesis Nutrition 2019

Objective The prevalence of obesity and related diseases such as type 2 diabetes mellitus (T2DM) is increasing worldwide, and the Asian Indian population seems to be particularly susceptible to developing T2DM, even at a low body mass index (BMI). In Sweden, the age-adjusted prevalence of diabetes has not increased despite increasing self-reported obesity. However, modern data on the prevalence of obesity and T2DM in Scandinavia are absent.The biochemical links between obesity and subsequent T2DM are unknown, but the adipocyte-derived hormones leptin and adiponectin (adipokines) have been suggested as potential links because they both are related to insulin and glucose physiology. Some studies have found leptin to be an independent predictor of T2DM in men but not in women, although these results are inconsistent. In contrast, adiponectin has more consistently been linked to development of T2DM in both men and women. Furthermore, the leptin–adiponectin ratio may predict incident T2DM better than either of the two hormones separately.The aims of this thesis were to describe time trends in obesity and T2DM in northern Sweden, to evaluate leptin and adiponectin as predictors of deterioration in glucose metabolism including T2DM, and to evaluate leptin as a risk marker regarding ethnic differences, circ-annual variation, and intra-individual stability. Materials and methods Three large population surveys were used, the Northern Sweden MONICA (MONitoring of Trends and Determinants in CArdiovascular Disease) study, the Västerbotten Intervention Programme (VIP), and the Mauritius Non-Communicable Disease Study. Within the MONICA study, six cross-sectional surveys were performed in Sweden’s two northernmost counties, Norrbotten and Västerbotten, between 1986 and 2009. A total of 1000 men and 1000 women ages 25–64 years, also including from 1994 250 men and 250 women ages 65–74 years, were independently chosen for each survey. The overall participation rate was 75%. In 1999, a reinvestigation was performed in 74% of all participants from the three first surveys. Data from the MONICA surveys were used in papers I and IV and data from the reinvestigation survey in paper II. VIP is an ongoing population intervention program that started in the mid-eighties targeting cardiovascular risk factors and has covered the whole county of Västerbotten since 1991. Inhabitants are invited the years they turn 40, 50, and 60 years old, and the annual participation rate has varied between 48% and 67%. A subset (n=1780) from VIP was used in paper II for the circ-annual leptin analysis, and VIP data linked to the diabetes register in Västerbotten (DiabNorr) were used in a case referent study (640 patients with T2DM) in paper III. The Mauritius Non-Communicable Disease Study was performed in 1987 in 10 randomly selected (with probability proportional to size) population clusters. All eligible adults ages 25–74 years were invited, and the participation rate was 86% (n=5083). In 1992, a follow-up survey was performed in 49% of the initial participants. The Mauritius survey data were used in paper II. Results I. BMI increased in men ages 25–74 years and in women ages 25–44 years in northern Sweden between 1986 and 2004. The prevalence of obesity (BMI 30) increased in men ages 25–44 and 55–74 years and in women ages 25–44 years. The prevalence of obesity increased from 10.4% to 19.1% in men and from 12.9% to 17.9% in women ages 25–64 years. Waist circumference (WC) decreased in women of all ages and in men ages 55–64 years between 1986 and 1990. After 1990, WC increased again, and the prevalence of abdominal obesity rose markedly in women ages 25–64 years. II. Differences in circulating levels of leptin, leptin per BMI unit (leptin/BMI), and leptin per cm in WC (leptin/waist) were tested in men and women of Asian Indian, Creole (African), and Caucasian ethnicity. Asian Indian men and women had the highest leptin concentrations and Caucasian men and women the lowest while Creole men and women had intermediate values for leptin, leptin/BMI, and leptin/waist. No circ-annual variation in leptin concentrations was seen in Caucasians. The intra-individual test– retest stability for leptin was equal in men and women of different ethnicities, over 5–13 years, with an intra-class correlation of 0.65–0.82. III. High adiponectin concentrations predicted decreased risk of T2DM in both insulin-sensitive and insulin-resistant men and women, whereas high leptin levels predicted increased risk for T2DM only in insulinsensitive men. A high leptin–adiponectin ratio predicted T2DM in both men and women, and men with a high ratio had a shorter time to diagnosis than those with a low ratio. IV. In northern Sweden, fasting and post-load glucose increased in women ages 24–65 years with 0.2 mmol/l and 0.7 mmol/l, respectively, between 1990 and 2009. Consequently, the prevalence of impaired fasting glucose and impaired glucose tolerance (IGT) rose from 4.5% to 7.7%, and from 7.8% to 14.5%, respectively. In men, post-load glucose increased at 0.5 mmol/l, and the prevalence of IGT rose from 3.5% to 10.1%. The prevalence of diabetes did not increase. An independent relationship between leptin and changes in fasting and post-load glucose was seen in men but not in women. Conclusion An increasing obesity and concomitant deterioration in glucose metabolism was seen in northern Sweden in the period studied. High adiponectin concentrations predicted a decreased risk of T2DM in both men and women, whereas high leptin concentrations predicted an increase in fasting and post-load glucose as well as an increased risk of T2DM in men but not in women. Individual insulin resistance status modified the association between leptin and T2DM, and the leptin–adiponectin ratio may add further predictive information beyond the measures of the separate hormones. In relation to traditional anthropometric measures of obesity, Asian Indian men and women had the highest and Caucasians the lowest concentrations of leptin while Creole (African) men and women had intermediate levels. As a risk marker, leptin has a high intra-individual stability, equal in men and women and among different ethnicities over 5–13 years with no circ-annual variation.

BACKGROUND: There is a dearth of studies on the association between diabetes mellitus (DM) and the risk of developing oral health complications in nonsmokers. Recent studies have presented a strong link between smoking and increased risk of periodontal disease in patients with T2DM. This study attempts to look at the risk of developing caries and poor oral health in nonsmokers who also have DM. Male and female subjects from the cross-sectional National Health and Nutrition Examination Survey (NHANES) 2017-2018 study who were 21+ years at the time of entering the study were included. The exposures are DM and smoking, and the outcome is oral health. HYPOTHESIS: DM-IFG will increase the risk of developing dental caries and tooth loss, thus lowering the quality of oral health in smokers compared to nonsmokers. METHODS: DM was defined as either the self-report of a doctor’s diagnosis of DM or a fasting glucose level of 126mg/dL or higher, or both. IFG was defined as a level of fasting glucose between 100mg/dL and 126mg/dL, as well as being informed by a medical doctor about having borderline DM. Subjects with IFG or DM were further combined into a DM-IFG group. Each subject’s status was classified on the basis of both DM-IFG status and smoking status, yielding four exposure groups: (1) no DM-IFG/non-smokers, (2) no DM-IFG/smokers, (3) DM-IFG/non-smokers, and (4) DM-IFG/smokers. Oral health outcomes were defined as a percent of missing teeth (due to dental health issues), percent of teeth with dental caries, and percent of teeth either missing or with caries. The primary statistical analysis for association between DM-IFG and smoking exposures and oral health outcomes was multivariable logistic regression. Adjusted models controlled for covariates such age, gender, Body Mass Index (BMI), education level, minutes of sedentary activity, race, HR, and percent of calories from fat intake. RESULTS: Overall, the prevalence of having 25% or more of teeth with dental caries was similar in those with and without DM-IFG (50.9% vs. 49.9%, respectively) and, surprisingly, was with higher among non-smokers than smokers (51.9% vs. 42.1%, respectively. Those with DM-IFG had a prevalence of missing teeth due to dental causes (≥ 15% missing) of 43.2% compared with a prevalence of 28.6% among those without DM-IFG. Since the majority of missing teeth were likely to be due to caries as well, the final outcome for these analyses consists of participants with either missing teeth or carious remaining teeth. Here, we found that 55.8% of those with DM-IFG had 40% of more of teeth missing vs. 44.8% of those without DM-IFG (p<0.0001). Similarly, 52.1% of smokers vs. 48.8% of non-smokers had more missing or carious teeth (p=0.1587). In the multivariable models, adjusting for age, race, HR, and percent of calories from fat, these analyses showed that DM-IFG alone (among non-smokers) was associated with a 1.42-fold increased risk of missing teeth while smoking along was associated with a 2.86-fold increased risk. The combined effects of the two factors were even stronger. Those who smoked cigarettes and who had DM-IFG (compared with those who did not smoke and had no DM-IFG) had a 3.88-fold increased risk of have 15% or more of their teeth missing due to dental health issues. Lastly, I examined these same effects on the risk of having either missing teeth or dental caries. In these analyses, smokers without DM-IFG had a 67% higher risk (95% CI: 1.27-2.19) of have 40% or more of their teeth missing or with caries while non-smokers with DM-IFG had no excess risk. Finally, those with DM-IFG who also smoked cigarettes had a 52% increased risk (95% CI: 1.08-2.14) of have 40% or more of their teeth missing or with caries compared with non-smokers who did not have DM-IFG. CONCLUSION: These results suggest that smoking was a more important risk factor for having missing teeth or dental caries than was DM or IFG.

No description available.

Over the past decade, there has been unprecedented increase in the number of genetic loci associating with type 2 diabetes (T2D) risk and related glycemic traits, thanks to advances in sequencing technologies and access to large sample sizes. Identification of associated genetic variants across the frequency spectrum can provide valuable insight into disease pathophysiology. However, the translation into biological insights has been slow often due to uncertainties over the underlying effector transcripts. G6PC2/ABCB11 is one locus characterised by common non-coding variants that are strongly associated with fasting plasma glucose (FG) levels in healthy adults. The work presented in this thesis aims to understand how protein-coding variants in glycemic trait loci such as G6PC2 contribute to the variability of glycemic traits and in addition gain further insight into the physiological role of G6PC2. To evaluate the role of coding variants in glycemic trait variation, an exome array genotyping study of non-diabetic European individuals (n=33,407) reported multiple coding variants in G6PC2 that were independently associated with FG. I designed and conducted in vitro assays to functionally assess these variants and showed that they result in loss of function (LOF) due to reduced protein stability. This established G6PC2 as the effector transcript influencing FG and highlighted a critical role for G6PC2 (encoding the islet-specific glucose-6-phosphatase catalytic subunit) in glucose homeostasis. To investigate the role of low frequency (MAF=1-5%) and rare (MAF&LT;1%) coding variants in influencing glycemic traits, recent large-scale exome array meta-analyses and whole exome sequencing were carried out as part of MAGIC (n=144,060) and the T2D-GENES/GoT2D consortia (n=12,940) respectively. G6PC1, a gene homolog of G6PC2 that primarily acts through the liver, was uncovered as a novel glycemic locus. My functional follow-up studies demonstrated that rare coding variants in G6PC1 exhibited LOF to influence both FG and FI levels. As rare variation in G6PC2 not previously identified could also affect G6PC2 function and modulate glycemic traits, I also functionally characterised a suite of rare non-synonymous G6PC2 variants. Most of the variants tested exhibited markedly reduced protein levels and/or loss of glycosylation. Several variants were also found to impact on enzymatic activity through inactivating or activating mechanisms to influence FG levels. Finally, to gain better understanding of the function of G6PC2 I performed gene knockdown studies in the EndoC-&beta;H1 human beta cell model followed by insulin secretion analyses. G6PC2 knockdown resulted in increased insulin secretion at sub-threshold glucose stimulation levels, consistent with studies in knockout mouse models. In addition, expression of LOF G6PC2 variants were found to upregulate ER stress responses. These results warrant further studies of the precise roles that G6PC2, an ER-resident protein, plays in regulating insulin secretory function and ER homeostasis in the beta cell. Overall, my work described multiple rare coding variants in both G6PC1 and G6PC2 that alter protein function to regulate glucose metabolism through diverse mechanisms in different tissues. Improved understanding of these effector transcripts will open up opportunities for the exploration of new therapeutic targets for glucose regulation and T2D.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第25170号 / 医博第5056号 / 新制||医||1071(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 山本 洋介, 教授 近藤 尚己, 教授 西浦 博 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DFAM

Background: This study was conducted to test the hypothesis that internal medicine residents at a northeast Tennessee university clinic were not compliant with the latest National Cholesterol Educational Program Adult Treatment Panel (NCEP-ATP) guidelines in treating hyperlipidemia in patients with diabetes and coronary artery disease. Methods: A retrospective medical record survey was conducted to evaluate residents' pattern in lowering low-density lipoprotein (LDL) cholesterol to below 100 mg/dL in patients with diabetes and coronary artery disease. The survey covered a 5-year period, from July 1998 to June 2003, and included 15 randomly chosen residents who were in training for 3 consecutive years. Charts were randomly selected from residents' clinics using International Classification of Diseases-9 codes for coronary artery disease or diabetes mellitus with hyperlipidemia. Five hundred fifty charts were reviewed. Only 41 (7.45%) met the inclusion criteria. Results: Analysis of data using Epi-Info 2002 (Centers for Disease Control and Prevention, Atlanta, GA) revealed that only 68.3% of patients with diabetes and coronary artery disease reached target LDL cholesterol levels. Of the patients who reached target levels, only 42.9% maintained them. Analysis of variance and chi-square tests revealed that the frequency of cholesterol measurement, but not the frequency of physicians' visits, was associated with a higher likelihood of reaching the target LDL level. Conclusion: There was a suboptimal compliance among internal medicine residents in the frequency of screening for, reaching, and maintaining the target LDL cholesterol level, according to the latest NCEP-ATP guidelines, among high-risk patients with hyperlipidemias.

Type 2 diabetes mellitus (T2DM) is a global health concern affecting six to ten percent of adults worldwide, with the number of diagnosed individuals projected to double in the next 25 years. However, effective public health strategies can help mitigate its impact on quality of life, morbidity, mortality and the associated social and economic burden. In Sweden, screening programs classify individuals with Impaired fasting glucose (IFG) as high-risk individuals, however scholars argue that preventative measures should also include those at lower fasting plasma glucose (FPG) concentrations as some evidence suggests that the disease begins developing several years before the current threshold. A systematic review and meta-analysis of cohort and case-control studies was conducted with the purpose of exploring the IFG threshold from a longitudinal perspective. Eleven studies on the incidence rates of T2DM in normoglycemic individuals and seven studies on pre-diagnostic trajectories of FPG concentrations were analyzed. Incidence rates increased progressively across the normoglycemic range, with a twelve-fold difference between the low and high end. FPG concentrations in eventual progressors and non-diabetic controls were significantly different twelve years prior to diagnosis. Mildly increasing FPG concentrations were observed in eventual progressors until three years before diagnosis, at which a larger increase followed. In the last year before diagnosis, FPG concentrations rose dramatically in this group. The findings imply that a lowering of the threshold would extend the time spent in the IFG state, allowing for earlier identification of at-risk individuals. In addition, further stratification of normoglycemic range may enhance the accuracy of T2DM risk assessment.