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Physical activity is important for the management and treatment of type 2 diabetes (T2D). Interval exercise training has been shown to improve glycemic control in people with T2D; however, studies have generally utilized high volume protocols and/or specialized equipment that limit translation to a “real world” setting. The present proof-of-concept study examined the efficacy of brief, intermittent stair climbing exercise to improve indices of glycemic control in adults with T2D, using continuous glucose monitoring (CGM) under controlled dietary conditions. Each session involved 3 x 60-s bouts of vigorously ascending and slowly descending a single flight of stairs. This was set within a 10-min period, which otherwise involved walking for a warm-up, cool-down and recovery in between bouts. Data are reported for n=5 participants (52 ± 18 y, BMI: 31 ± 5 kg/m2, HbA1c: 6.6 ± 0.7 %; mean ± SD) who performed 18 training sessions over 6 weeks. Mean 24-h glucose and time spent in hyperglycemia (> 10 mmol/L) were unchanged after an acute session of stair climbing (p=0.38 and p=0.42, respectively) or after 6 weeks of training (p=0.15 and p=0.47, respectively). Measures of glycemic variability were improved in the 24-h period following a single session of stair climbing, based on reductions in the mean amplitude of glycemic excursions (MAGE) (4.4 ± 1.5 vs. 3.5 ± 1.0 mmol/L, p =0.02) and the standard deviation (SD) around the mean (1.7 ± 0.5 vs. 1.4 ± 0.5 mmol/L, p=0.02). There was a meal-specific improvement in postprandial hyperglycemia after training, with the incremental area under the curve (iAUC) of the lunchtime meal reduced by 36 ± 42 % (p=0.01). These preliminary results demonstrate the feasibility of stair climbing as a physical activity option for people with T2D, although the acute and chronic effects of this training on indices of glycemic control remain equivocal. / Thesis / Master of Science in Kinesiology / Physical activity is important for the management of type 2 diabetes (T2D). Interval training, which involves alternating periods of relatively intense exercise and recovery, can improve blood sugar control in adults with T2D. This has largely been shown in laboratory settings using specialized equipment and protocols that may not be practical or time-efficient. This small, proof-of-concept study examined whether brief, intermittent stair climbing exercise could improve blood sugar control in people with T2D. Average blood sugar measured over 24 hours was unchanged after a single bout of stair climbing and after 18 sessions of training performed over 6 weeks. However, stair-climbing exercise reduced blood sugar fluctuations in response to specific meals. These preliminary findings suggest that interval stair climbing is a feasible exercise option for adults with T2D, but the precise effects on blood sugar control remain to be clarified.

Background: Diabetes is an important cause of morbidity, mortality, and health-system costs worldwide. The growing burden of T2DM particularly in developing countries has directed more attention to primary prevention. This cross-sectional study assessed the prevalence of T2DM and its risk factors among general and diabetic populations of the Zamboanga Peninsula, Philippines. Methods: This was a multi-center community-based cross-sectional study. 2624 individuals 40 years old or older residents (100 persons per Barangay of total 26 barangays) of the Zamboanga Peninsula province have been chosen via door-to-door systematic random sampling procedure. Personal demographic, anthropometric and lifestyle information was collected using a structured questionnaire. Weight, height, WC, BMI, and HbA1c test was were obtained through participant measurements. Results: Valid data of 2572 (98.01%) individuals analyzed, mean ±SD of age was 57.39 ± 10.41 and 1843 (71.7%) of participants were women. Based on ADA 2018 guideline, the prevalence of T2DM and prediabetes were 18.3% and 26.7%, respectively. The frequency of having T2DM and prediabetes was higher in older people (p< 0.05). Urban areas had a significantly higher prevalence of diabetes, prediabetes compared with rural areas (p< 0.01). 54.4 % of the population had a normal body mass index while 45.6% of the population were overweight (32.1 %) or obese (13.5%), and 65% had high or elevated WC. There was a significant association between BMI /central obesity and glucose abnormalities (P<0.01). The prevalence of overweight, obesity and abdominal obesity was significantly higher in women and the older age groups had significantly lower BMIs/ abdominal obesity than younger age groups. 40.4% of the participants had HTN and the prevalence of HTN was significantly higher in the older age groups and female participants. The prevalence of HTN and family history of diabetes were higher in T2DM patients and individuals with prediabetes (P<0.01). Based on the FINDRISC score, the risk of developing diabetes was high or very high in 17.6% and moderate in 20.0% of the population. Conclusion: The prevalence of T2DM and prediabetes was higher in this study compared to previous surveys in the country. This finding highlights the need for public health efforts to improve T2DM risk factors such as obesity and hypertension in this population. / Thesis / Master of Science (MSc)

Obesity is characterized by hyperinsulinemia and chronic inflammation, contributing to insulin resistance and type 2 diabetes (T2D) risk. Pattern recognition receptors (PRRs) of the innate immune system, including Toll-like Receptors (TLRs) and Nod-like Receptors (NLRs), have been identified as propagators of metabolic inflammation. Circulating bacterial components exert distinct effects on inflammation and insulin sensitivity via TLRs and NLRs. Specific types of bacterial peptidoglycan engage NOD1 and NOD2. Activators of NOD1 increase inflammation and insulin resistance, while activators of NOD2 promote immune tolerance and insulin sensitivity. NOD1 and NOD2 use the common downstream adaptor RIPK2 to drive immune responses, but the role of RIPK2 in glucose homeostasis was unknown. RIPK2 is positioned to mediate effects of xenobiotics and microbial components on blood glucose. For example, tyrosine kinase inhibitors (TKIs) are being investigated for diabetes treatment. Improvements in blood glucose control have been observed in diabetic cancer patients receiving TKI therapy but the mechanism underlying these changes remains unclear. Several TKIs inhibit RIPK2. We sought to understand if TKIs that inhibit RIPK2 block inflammatory and metabolic consequences of NOD signalling. We hypothesized inhibition of inflammation via NOD1-RIPK2 by certain TKIs contributes to lowered blood glucose/improved insulin sensitivity in pre-clinical models of obesity. We showed that RIPK2 was required for acute glycemic consequences of NOD1 and NOD2 activation, and RIPK2-specific TKIs attenuated these glycemic effects. We found TKI-mediated improvements in blood glucose are independent of NOD-RIPK2 signalling during diet-induced obesity. However, RIPK2 mediated the effects of certain TKIs on blood insulin. Finally, we tested if RIPK2 mediated the effects of bacterial components derived from commensal microbiota. We found injection of upper intestinal microbe components lowered blood glucose via NOD2-RIPK2 signalling. These findings demonstrate that modulation of RIPK2 signalling by xenobiotic or microbial factors is an important contributor to blood glucose and insulin homeostasis. / Thesis / Doctor of Philosophy (PhD) / Obesity increases the risk of chronic diseases, including Type 2 Diabetes (T2D). Obesity stops insulin from working properly, leading to the inability to lower blood glucose. Obesity and T2D are linked to chronic, low-grade activation of the immune system. The immune system normally defends the body against microbes by inducing a pro-inflammatory response. Inflammation can also be activated or inhibited by drugs (xenobiotics), and different aspects of inflammation can increase or decrease blood glucose and insulin. A major unanswered question was how certain cancer drugs and bacterial components interact with the immune system to change blood glucose or insulin. This work tested how an innate immune pathway that detects bacterial cell wall components is influenced by cancer drugs and alters blood glucose and insulin in pre-clinical models. This work is targeted at understanding how new prebiotics or existing drugs can be tasked as therapeutic strategies for prediabetes and T2D.

Indiana University-Purdue University Indianapolis (IUPUI) / Type-2-diabetes (T2D) is a progressive metabolic disease characterized by insulin resistance and β-cell dysfunction leading to persistent hyperglycemia. It is a multisystem disease that causes deterioration of multiple organ systems and obesity. Of interest, T2D affects the urinary system and is the leading cause of kidney disease. Both T2D and chronic kidney negatively impacts the skeletal system and increases fracture incidence in patients. Therefore, it is important to establish an animal model that captures the complex multiorgan effects that is common in T2D. In this study, we characterized the metabolic phenotype of the KK/Ay mouse model, a polygenic mutation model of T2D. We concluded that KK/Ay mice closely mimic T2D and are hyperglycemic, hyperinsulinemic and insulin resistant. KK/Ay mice have also had worsened kidney function as supported by elevated levels of blood urea nitrogen, phosphorous, creatinine, and calcium in plasma exhibiting the kidney’s inefficiency in clearing waste from the body. Even though we were able to confirm a metabolic phenotype for T2D and diabetic nephropathy, the skeletal effects of the disease were minimal and major differences in bone physiology were driven by sex differences. This study offered valuable insight into preliminary endpoints for the KK/Ay mouse mode that will decide the direction for future use of this model. We plan to use older mice in future studies to allow a longer time for skeletal effects to more prominently manifest.

Physical inactivity is a major contributor to increased disease prevalence and reduced quality of life. Measuring behavioral economic demand for exercise may enable more effective physical activity intervention development. In study one, we developed the leisure-time-as-price exercise purchase task (LT-EPT), wherein participants (n = 175) indicate hypothetical likelihood to trade leisure time for access to exercise time. We observed weak to moderate correlations between demand indices (Q1%, α, BP1, and Pmax) generated from the LT-EPT and self-reported leisure and exercise time, demonstrating initial validation of the LT-EPT. In study two, we examine the effect of episodic future thinking (EFT; vivid, personalized prospection of future events) in adults not meeting physical activity guidelines (n = 127) on demand for exercise and delay discounting (sensitivity to delayed rewards). We observed reduced delay discounting in participants randomized to engage in EFT, but no difference between EFT and health information thinking (HIT) controls. In study three, we further examined the effect of EFT on demand for exercise in adults with type 2 diabetes and obesity participating in a 24-week randomized controlled trial (n = 71). All participants engaged in a multicomponent behavioral intervention focused on weight loss and glycemic control; additionally, participants were randomized to engage in EFT or HIT thrice daily beginning in week 3. We measured demand for exercise and delay discounting (among other outcomes) at weeks 0, 8, and 24, observing no differences between EFT or HIT groups in demand indices (Q1%, α) or delay discounting at any time point. In conclusion, early evidence suggests that the LT-EPT may be a valid method to measure behavioral economic demand for exercise; however, EFT may not be an effective intervention to increase demand for exercise. / Doctor of Philosophy / Physical inactivity poses a significant threat to our well-being, contributing to increased disease rates and a diminished quality of life. This dissertation details a novel method to measure how people value exercise and the effect of a behavioral intervention to increase exercise valuation. In the first study, we introduce the leisure-time-as-price exercise purchase task (LT-EPT), a tool designed to gauge individuals' willingness to trade leisure time for exercise time (i.e., exercise demand). Initial results show promising correlations between LT-EPT metrics and self-reported leisure and exercise time, providing a foundation for its potential as a valuable measurement tool. The second study examines the impact of episodic future thinking (EFT), a technique involving vivid and personalized visualization of future events, on exercise demand. While participants engaging in EFT showed increased preference for larger, delayed rewards over smaller, sooner rewards (i.e., reduced delay discounting), no significant difference was found between EFT and the health information thinking (HIT) control in terms of exercise demand. The third study expands our investigation to adults with type 2 diabetes and obesity undergoing a 24-week intervention. All participants engaged in a comprehensive behavioral program, while half were randomized to engage in EFT or HIT three times per day. No discernible differences were observed in exercise demand or delay discounting at any measurement point. In summary, our findings suggest that the LT-EPT may be a valid measure of exercise demand. However, the effectiveness of EFT in increasing demand for exercise remains inconclusive. These insights contribute to the ongoing efforts to develop more targeted and impactful interventions for promoting physical activity and improving overall health.

Healthcare agencies and researchers identify several areas in which healthcare disparity affects elder, African-American diabetics including higher rates of diagnosis, higher limb amputation, increased kidney failure, and stroke. While the disparities have been documented, elder, African-American diabetics rarely have been invited into discussions concerning these disparities, research questions, project or program design, and results. They are not asked to be stakeholders in health care or health policy discussions. This study used grounded theory as a participatory action research method to invite elder, African-American, diabetics into the discussion using focus groups. The patient participants then suggested providers they believed to be "successful" in their care who were then interviewed. The analysis suggests that where patient/ provider communication has been peripheral that care and perception of care and patient suffer. Where successful communication was central to the patient/provider relationship, provider preconceptions lessened and patient compliance levels rose. This dissertation offers several downstream, midstream, and upstream recommendations using a patient-focused lens. / Ph. D.

Currently, it is reported that ~65% and 34% of the U.S. population is overweight and obese, respectively. Obesity is a major risk factor for cardiovascular disease. Overweight and obese individuals are also at an increased risk of developing hypertension. Whole-body insulin sensitivity is reduced in obesity, resulting in insulin resistance and increased risk of type 2 diabetes. One possible mechanism contributing to insulin resistance in obesity hypertension is renin-angiotensin system (RAS) overactivation. The RAS exhibits vasocontricting and sodium-retaining properties, yet in vivo and in vitro animal experiments suggest impairment of whole-body insulin sensitivity with increased angiotensin II (Ang II) exposure. Furthermore, evidence from clinical studies indicates Ang II receptor blockers (ARBs) may reduce the incidence of new-onset diabetes compared to other antihypertensive agents in at-risk hypertensive patients. However, it is unclear if whole-body insulin sensitivity is improved with Ang II receptor blockade in humans. Thus, we tested the hypothesis that 8-week Ang II receptor blockade with olmesartan would improve whole-body insulin sensitivity in overweight and obese individuals with elevated blood pressure (BP). Olmesartan was selected for the present study because it is devoid of partial PPARγ agonist activity. To test our hypothesis, intravenous glucose tolerance tests were performed to measure insulin sensitivity before and after control and ARB treatment in a randomized crossover manner. Because skeletal muscle tissue accounts for ~75-90% of insulin-stimulated glucose uptake, a secondary exploratory aim was to examine skeletal muscle inflammatory and collagen response in relation to insulin sensitivity during ARB treatment. No baseline differences were observed between treatments (P>0.05). Both systolic (-11.7 mmHg; P=0.008) and diastolic (-12.1 mmHg; P=0.000) BP were reduced with ARB treatment. Insulin sensitivity was not different between treatments (P>0.05). No correlates of insulin sensitivity were identified. In addition, skeletal muscle inflammatory and collagen gene expression did not change from pre- to post-ARB treatment (P>0.05). Our findings suggest that short-term RAS blockade in overweight and obese adults with elevated BP does not improve whole-body insulin sensitivity, despite a significant BP reduction. Further studies are needed to clarify the role of individual RAS blockers on insulin sensitivity during RAS inhibition in obesity hypertension. / Ph. D.

Purpose: To determine if a quality improvement project involving individualized, one-on-one Diabetes education will improve health literacy and Diabetes outcomes in adults with Type 2 Diabetes in a rural primary care clinic. Diabetes is a chronic condition affecting the United States with 9.6% of Virginia’s population living with Diabetes. Aims: To improve patient’s Diabetes literacy scores, BMI, and Hemoglobin A1c levels through Diabetes education. Processes: There are pre- and post-education phases. Data to be collected at the end of both phases consist of DNT15 scores, BMI, and A1c. In the pre-education phase, BMI was obtained, DNT15 was administered, and Diabetes education was provided. Then, A1c was obtained, and patients were scheduled to return in the month of May. Post-education phase starts at the follow-up where participants retake DNT15 and BMI and A1c will be obtained. Results: Only pre-education data has been collected from the participants. Post-education data will be collected throughout the month of May during 3-month follow-up appointments. Expected results include 10% improvement of BMI, A1C, and Diabetes literacy scores. Limitations: Increased use of GLP1 prescriptions in clinic could affect results. Some patients were sent to the ED after being seen requiring prompt follow-ups while others obtain A1c results from other disciplines and may not have results sent to this clinic by the end of the data collection period. There have also been several no shows. Patients and staff have been receptive to the quality improvement initiative. Conclusion: Education has been provided to 25 patients. Follow-ups are scheduled for post-education data collection in May.

Yes / Introduction Type 2 diabetes mellitus (T2DM) promotes adverse myocardial remodeling and increased risk of heart failure; effects that can occur independently of hypertension or coronary artery disease. As cardiac fibroblasts (CFs) are key effectors of myocardial remodeling, we investigated whether inherent phenotypic differences exist in CF derived from T2DM donors compared with cells from nondiabetic (ND) donors. Methods Cell morphology (cell area), proliferation (cell counting over 7-day period), insulin signaling [phospho-Akt and phospho-extracellular signal-regulated kinase (ERK) Western blotting], and mRNA expression of key remodeling genes [real-time reverse transcription-polymerase chain reaction (RT-PCR)] were compared in CF cultured from atrial tissue from 14 ND and 12 T2DM donors undergoing elective coronary artery bypass surgery. Results The major finding was that Type I collagen (COL1A1) mRNA levels were significantly elevated by twofold in cells derived from T2DM donors compared with those from ND donors; changes reflected at the protein level. T2DM cells had similar proliferation rates but a greater variation in cell size and a trend towards increased cell area compared with ND cells. Insulin-induced Akt and ERK phosphorylation were similar in the two cohorts of cells. Conclusion CF from T2DM individuals possess an inherent profibrotic phenotype that may help to explain the augmented cardiac fibrosis observed in diabetic patients.