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These studies investigated the effect of physical inactivity (prolonged sitting) and physical activity (walking, standing, and moderate intensity exercise) on postprandial plasma triglyceride concentration (PPTG). In the first study, we evaluated the effect of low intensity intermittent walking at ~25% VO₂max (WALK) and energy-matched moderate intensity running at ~65% VO₂max (RUN) on PPTG, compared to a sitting control (SIT). RUN reduced incremental area under the curves for plasma triglyceride concentration (TG AUC[subscript I]), compared to WALK by 17.3% (p = 0.04) and SIT by 27% (p [less than] 0.001). The reduced TG AUC[subscript I] in RUN was accompanied by enhanced whole body insulin sensitivity, compared to WALK and SIT (for both, p [less than] 0.05). Whole body postprandial fat oxidation at rest following a high fat test meal intake was enhanced in RUN by 31% (P [less than] 0.001) and to a lesser extent in WALK by 8.4% (p [less than] 0.005), compared to SIT. In the second study, we evaluated 1) the effect of 2 days of prolonged sitting on PPTG, and 2) the effect of 4 days of SIT on the ability of an acute bout of exercise to reduce PPTG, compared to the same days of active walking and standing with calorically balanced diet (WALK+B). To distinguish the effect of prolonged sitting from the excess calorie effect, we had a sitting condition with calorically balanced diet (SIT+B) in addition to a sitting condition with hypercaloric diet (SIT+H). Following 2 days of respective food and activity control, WALK+B was lower in TG AUC[subscript T] by 21.3% and AUC[subscript I] by 17.4%, compared to SIT+H (for both, p [less than] 0.005). WALK+B was lower than SIT+B for TG AUC[subscript T] by 17.7% (p = 0.165) and AUC[subscript I] by 23.5% (p = 0.145) although statistical significance was not achieved. Remarkably, an acute exercise following 4 days of either SIT+H or SIT+B failed to reduce both TG AUC[subscript T] and AUC[subscript I], compared to SIT+B in HFTT1. The same exercise following 4 days of WALK+B, however, reduced both TG AUC[subscript T] by 29% and TG AUC[subscript I] by 32% in HFTT2, compared to SIT+B in HFTT1 (for both, p [less than] 0.02). Further, both SIT conditions reduced relative whole body fat oxidation in favor of increases in carbohydrate oxidation, compared to WALK+B by more than 40% in both HFTT1 and HFTT2. Taken together, our data suggest that 1) exercise intensity plays an independent role with higher intensity being more effective than lower intensity exercise in reducing PPTG, and 2) prolonged sitting with excess energy intake amplifies PPTG and prolonged sitting impairs the ability of an acute bout of moderate intensity exercise to reduce PPTG. This emphasizes the importance of regular participation in moderate-to-vigorous intensity exercise and reducing sitting time by increasing non-exercise physical activities (i.e., walking and standing) for the favorable postprandial metabolic health from the individual and public health perspectives. / text

Both obesity and type 2 diabetes are significant health burdens in our society. The prevention of these conditions is vital to individual health and to the health care system, which is inordinately stressed by these chronic diseases. Due to variations in individual response to interventions, prevention strategies may require some tailoring based on heritable traits.The objective of this study was to determine whether insulin sensitivity could be altered by resistance training, and further if body composition or insulin sensitivity response to resistance training in postmenopausal women may be influenced by adrenergic receptor genetic variants and gene-gene interactions.Completers of a 12-month randomized controlled trial of resistance training in sedentary post-menopausal (PM) women, using or not using hormone therapy, were measured for fasting plasma glucose, insulin, and non-esterified fatty acids (NEFA) at baseline and one year. These biomarkers were used to compute models of insulin sensitivity. Body composition was measured by dual x-ray absorptiometry. Subjects were also re-consented for genotyping of adrenergic receptor (ADR) gene variants, ADRA2B Glu9/12, ADRB3 Trp64Arg, ADRB2 Gln27Glu.The resistance training intervention did not have an overall effect on insulin sensitivity in the largest sample and change in insulin sensitivity was largely dependent body composition. There were small favorable effects of genotype on initial measures of both body composition and insulin sensitivity in the ADRA2B Glu9+ carriers versus non-carriers. The effects of ADRA2B alone were no longer present following intervention, but ADRB3 Arg64+ and ADRB2 Glu27+ contribute to improved insulin sensitivity with exercise, when accounting for body composition. ADRB2 Glu27+ was the key to improved biomarkers of insulin sensitivity when in combination with ADRA2B Glu9+ or ADRB3 Arg64+ and a model of insulin sensitivity was most improved by the combination ADRB3 Arg64+ by ADRB2 Glu27+, compared to other ADRB3 by ADRB2 combinations.This is the first trial of ADRA2B, ADRB3, and ADRB2 genetic variation combinations and resistance training in postmenopausal women relative to body composition and insulin sensitivity. Some specific genotypes were identified as responders and non-responders to exercise. These data support independent associations between body composition and insulin sensitivity and the ADR gene variants.

Individuals with abdominal obesity are at higher risk for developing type 2 diabetes, predisposing cardiovascular events and insulin resistance. Low glycemic index (GI) diets may be beneficial in the management of insulin resistance. Insulin resistance is associated with increased intramyocellular lipid (IMCL) content as measured by proton nuclear magnetic resonance spectroscopy (1H-MRS). The primary objective of this thesis was to determine whether a low GI diet can improve insulin sensitivity by reducing IMCL of skeletal muscle. One hundred and twenty-one male and female participants aged 30 to 70 years (mean+SD, 53+10)) with abdominal obesity, entered a 4 to 6 week weight-maintaining, low-fat dietary advice run-in phase. Of the 121 eligible participants, 95 completed the run-in phase and were randomly assigned to either a low-GI (LGID, n=48) or high-GI diet (HGID, n=47) for 24 weeks. Participants underwent a 75g oral glucose tolerance test (OGTT) and had soleus-muscle IMCL measured by 1H-MRS at the beginning and end of the intervention period. Insulin sensitivity was assessed by the homeostatic model assessment index (HOMA) and the insulinogenic index (ISI) was calculated for insulin secretion. At the end of the run-in phase, there were significant reductions in serum total-, LDL-, and HDL-cholesterol (all, p<0.0001) and an increase in fasting plasma glucose (p<0.05). In 57 participants who wore a continuous glucose monitoring system for 24 hours during the run-in period, a total of 30% (p<0.001) of the variation in the incremental area under the blood glucose curve after self-selected breakfast meals was explained by GI. After 24 weeks, diet GI was significantly lower in the LGID than HGID group (55.5+3.1 vs 63.9+3.1, p<0.0001). Plasma glucose 60 minutes after the OGTT was significantly lower on the LGID than at baseline (p<0.05) and there was a non-significant trend towards an increase in ISI (p=0.07). On the HGID, ISI increased significantly from baseline (p<0.01). It is concluded that the LGID reduced 60 minute plasma glucose but did not significantly affect IMCL or insulin sensitivity in individuals with abdominal obesity.

Individuals with abdominal obesity are at higher risk for developing type 2 diabetes, predisposing cardiovascular events and insulin resistance. Low glycemic index (GI) diets may be beneficial in the management of insulin resistance. Insulin resistance is associated with increased intramyocellular lipid (IMCL) content as measured by proton nuclear magnetic resonance spectroscopy (1H-MRS). The primary objective of this thesis was to determine whether a low GI diet can improve insulin sensitivity by reducing IMCL of skeletal muscle. One hundred and twenty-one male and female participants aged 30 to 70 years (mean+SD, 53+10)) with abdominal obesity, entered a 4 to 6 week weight-maintaining, low-fat dietary advice run-in phase. Of the 121 eligible participants, 95 completed the run-in phase and were randomly assigned to either a low-GI (LGID, n=48) or high-GI diet (HGID, n=47) for 24 weeks. Participants underwent a 75g oral glucose tolerance test (OGTT) and had soleus-muscle IMCL measured by 1H-MRS at the beginning and end of the intervention period. Insulin sensitivity was assessed by the homeostatic model assessment index (HOMA) and the insulinogenic index (ISI) was calculated for insulin secretion. At the end of the run-in phase, there were significant reductions in serum total-, LDL-, and HDL-cholesterol (all, p<0.0001) and an increase in fasting plasma glucose (p<0.05). In 57 participants who wore a continuous glucose monitoring system for 24 hours during the run-in period, a total of 30% (p<0.001) of the variation in the incremental area under the blood glucose curve after self-selected breakfast meals was explained by GI. After 24 weeks, diet GI was significantly lower in the LGID than HGID group (55.5+3.1 vs 63.9+3.1, p<0.0001). Plasma glucose 60 minutes after the OGTT was significantly lower on the LGID than at baseline (p<0.05) and there was a non-significant trend towards an increase in ISI (p=0.07). On the HGID, ISI increased significantly from baseline (p<0.01). It is concluded that the LGID reduced 60 minute plasma glucose but did not significantly affect IMCL or insulin sensitivity in individuals with abdominal obesity.

Hyperglycemia is prevalent in critical care, as patients experience stress-induced hyperglycemia, even with no history of diabetes. Hyperglycemia has a significant impact on patient mortality, outcome and health care cost. Tight regulation can significantly reduce these negative outcomes, but achieving it remains clinically elusive, particularly with regard to what constitutes tight control and what protocols are optimal in terms of results and clinical effort. Hyperglycemia in critical care is not largely benign, as once thought, and has a deleterious effect on outcome. Recent studies have shown that tight glucose regulation to average levels from 6.1–7.75 mmol/L can reduce mortality 17–45%, while also significantly reducing other negative clinical outcomes. However, clinical results are highly variable and there is little agreement on what levels of performance can be achieved and how to achieve them. A typical clinical solution is to use ad-hoc protocols based primarily on experience, where large amounts of insulin, up to 50 U/hr, are titrated against glucose measurements variably taken every 1–4 hours. When combined with the unpredictable and sudden metabolic changes that characterise this aspect of critical illness and/or clinical changes in nutritional support, this approach results in highly variable blood glucose levels. The overall result is sustained periods of hyper- or hypo- glycemia, characterised by oscillations between these states, which can adversely affect clinical outcomes and mortality. The situation is exacerbated by exogenous nutritional support regimes with high dextrose content. Model-based predictive control can deliver patient specific and adaptive control, ideal for such a highly dynamic problem. A simple, effective physiological model is presented in this thesis, focusing strongly on clinical control feasibility. This model has three compartments for glucose utilisation, interstitial insulin and its transport, and insulin kinetics in blood plasma. There are two patient specific parameters, the endogenous glucose removal and insulin sensitivity. A novel integral-based parameter identification enables fast and accurate real-time model adaptation to individual patients and patient condition. Three stages of control algorithm developments were trialed clinically in the Christchurch Hospital Department of Intensive Care Medicine. These control protocols are adaptive and patient specific. It is found that glycemic control utilising both insulin and nutrition interventions is most effective. The third stage of protocol development, SPRINT, achieved 61% of patient blood glucose measurements within the 4–6.1 mmol/L desirable glycemic control range in 165 patients. In addition, 89% were within the 4–7.75 mmol/L clinical acceptable range. These values are percentages of the total number of measurements, of which 47% are two-hourly, and the rest are hourly. These results showed unprecedented tight glycemic control in the critical care, but still struggle with patient variability and dynamics. Two stochastic models of insulin sensitivity for the critically ill population are derived and presented in this thesis. These models reveal the highly dynamic variation in insulin sensitivity under critical illness. The stochastic models can deliver probability intervals to support clinical control interventions. Hypoglycemia can thus be further avoided with the probability interval guided intervention assessments. This stochastic approach brings glycemic control to a more knowledge and intelligible level. In “virtual patient” simulation studies, 72% of glycemic levels were within the 4–6.1 mmol/L desirable glycemic control range. The incidence level of hypoglycemia was reduced to practically zero. These results suggest the clinical advances the stochastic model can bring. In addition, the stochastic models reflect the critical patients’ insulin sensitivity driven dynamics. Consequently, the models can create virtual patients to simulated clinical conditions. Thus, protocol developments can be optimised with guaranteed patient safety. Finally, the work presented in this thesis can act as a starting point for many other glycemic control problems in other environments. These areas include the cardiac critical care and neonatal critical care that share the most similarities to the environment studied in this thesis, to general diabetes where the population is growing exponentially world wide. Furthermore, the same pharmacodynamic modelling and control concept can be applied to other human pharmacodynamic control problems. In particular, stochastic modelling can bring added knowledge to these control systems. Eventually, this added knowledge can lead clinical developments from protocol simulations to better clinical decision making.

Type 2 diabetes has reached epidemic proportions worldwide. The resulting increase in chronic and costly diabetes related complications has potentially catastrophic implications for healthcare systems, and economies and societies as a whole. One of the key pathological factors leading to type 2 diabetes is insulin resistance (IR), which is the reduced or impaired ability of the body to make use of available insulin to maintain normal blood glucose levels. Diagnosis of developing IR is possible up to 10 years before the diagnosis of type 2 diabetes, providing an invaluable opportunity to intervene and prevent or delay the onset of the disease. However, an accurate, yet simple, test to provide a widespread clinically feasible early diagnosis of IR is not yet available. Current clinically practicable tests cannot yield more than a crude surrogate metric that allows only a threshold-based assessment of an underlying disorder, and thus delay its diagnosis. This thesis develops, analyses and pilots a model-based insulin sensitivity test that is simple, short, physiological and cost efficient. It is thus useful in a practical clinical setting for wider clinical screening. The method incorporates physiological knowledge and modelling of glucose, insulin and C-peptide kinetics and their pharmaco-dynamics. The clinical protocol is designed to produce data from a dynamic perturbation of the metabolic system that enables a unique physiologically valid assessment of metabolic status. A combination of a-priori information and a convex integral-based identification method guarantee a unique, robust and automated identification of model parameters. In addition to a high resolution insulin sensitivity metric, the test also yields a clinically valuable and accurate assessment of pancreatic function, which is also a good indicator of the progression of the metabolic defect. The combination of these two diagnostic metrics allow a clinical assessment of a more complete picture of the overall metabolic dysfunction. This outcome can assist the clinician in providing an earlier and much improved diagnosis of insulin resistance and metabolic status and thus more optimised treatment options. Test protocol accuracy is first evaluated in Monte Carlo simulations and subsequently in a clinical pilot study. Both validations yield comparable results in repeatability and robustness. Repeatability and resolution of the test metrics are very high, particularly when compared to current clinical standard surrogate fasting or oral glucose tolerance assessments. Additionally, the model based insulin sensitivity metric is shown to be highly correlated to the highly complex, research focused gold standard euglycaemic clamp test. Various reduced sample and shortened protocols are also proposed to enable effective application of the test in a wider range of clinical and laboratory settings. Overall, test time can be as short as 30 minutes with no compromise in diagnostic performance. A suite of tests is thus created and made available to match varying clinical and research requirements in terms of accuracy, intensity and cost. Comparison between metrics obtained from all protocols is possible, as they measure the same underlying effects with identical model-based assumptions. Finally, the proposed insulin sensitivity test in all its forms is well suited for clinical use. The diagnostic value of the test can assist clinical diagnosis, improve treatment, and provide for higher resolution and earlier diagnosis than currently existing clinical and research standards. High risk populations can therefore be diagnosed much earlier and the onset of complications delayed. The net result will thus improve overall healthcare, reduce costs and save lives.

Equine pituitary pars intermedia dysfunction (PPID) typically occurs in horses older than 15 years of age and is characterized by hair coat abnormalities, muscle atrophy and decreased insulin sensitivity. The first objective of this research was to compare the rate of whole body protein metabolism and relative abundance of key factors in the signaling pathways associated with muscle protein synthesis and protein breakdown in response to feeding in Control and PPID horses. No differences (P > 0.05) were seen between the PPID and Control groups in whole-body protein metabolism or post-prandial activation of the muscle signaling pathways regulating skeletal muscle protein synthesis and breakdown. The second objective of this research was to determine if aged horses with PPID had reduced insulin sensitivity and alterations in the insulin-mediated signaling pathways in the skeletal muscle when compared to non-PPID, aged Control horses. Measures of insulin sensitivity and the activation of factors associated with protein synthesis and breakdown were similar between the PPID and Control groups (P > 0.05). Overall, insulin sensitivity and protein metabolism are similar between the PPID and Control groups. The studies suggest that abnormalities may exist as a function of advanced age rather than PPID status directly.

ABSTRACT Insulin Dynamic Measures and Weight Change By Noreen Kloc B.S. Computer Information Technology, Purdue University December 7, 2015 INTRODUCTION: Weight gain and obesity are risk factors for insulin resistance that can lead to type 2 diabetes and cardiovascular disease; however, there is a complicated interplay between insulin sensitivity (SI), fasting insulin, acute insulin response (AIR), and disposition index (DI) and the relationship of these dynamic measures with weight change is not well understood. AIM: The aim of this study was to investigate the relationships between insulin dynamic measures, SI, fasting insulin, AIR, and DI, with weight change during a 5-years follow-up period in the multi-ethnic cohort of the Insulin Resistance Atherosclerosis Study (IRAS). METHODS: Data on 879 men and women of Hispanic, non-Hispanic White, and African-American race/ethnicity aged 40-69 years were obtained at baseline (1992-1994) and at 5 year follow-up. Crude associations between the insulin dynamic measures and weight change were evaluated using Kruskal-Wallis test and the relationships between log-transformed insulin-related variables were examined using Spearman rank-order analysis. Multivariate regression models evaluated associations of interest adjusted for age, sex, ethnicity, and diabetes status in a time-dependent manner using mixed models. RESULTS: Insulin sensitivity SI inversely coevolves with weight, i.e. greater weight is predicted by lower SI at any time point. To answer the question whether SI is the cause or a consequence of weight change, we examined the associations with the baseline values and a change in SI. In this model, both the baseline SI and change in SI were inversely correlated with weight gain. A similar approach showed that baseline values and change in fasting insulin were directly associated with weight gain. Weight change over time was associated with AIR, i.e. increases in AIR and greater AIR at baseline predicted weight gain. We did not find strong relationships between DI and weight change. DISCUSSION: These results suggest that insulin sensitivity and insulin secretion can modulate weight in a non-diabetic population.

Cardiovascular disease (CVD) and type two diabetes mellitus (T2D) are among the leading causes of death worldwide. Insulin resistance (IR) and hyperglycaemia are risk factors for CVD and T2D and are known to be prevalent in youth. Physical activity (PA) is known to improve IR and glucose tolerance in youth, but current levels of PA are low meaning alternative PA recommendations are needed. The purpose of this thesis is to investigate the effect of low volume high-intensity interval exercise (HIIE) on insulin and glucose health outcomes in male children and adolescents. Additionally, the thesis will explore the potential for HIIE to improve glycaemic control in paediatric patients with type one diabetes mellitus (T1D). Chapter 4 examines the relationship between estimates of insulin sensitivity (IS) based on oral glucose tolerance test (OGTT) and fasted assessment methods, in addition to the day-to-day reliability of these measures in children and adolescents. Results from this chapter advocated the Cederholm index to measure IS in this sample due to the low day to day reliability (coefficient of variation (%CV) of 6.4%). Chapter 5 demonstrates comparable results, reporting moderate improvements to IS and glucose tolerance measured via an OGTT 10 minutes after a single bout of HIIE and work-matched moderate-intensity exercise (MIE) in adolescent boys (13-15 y old). The findings from Chapter 5 are extended in Chapter 6, where changes to OGTT derived IS and glucose tolerance were measured up to 24 h post exercise and fasting measures of IS up to 48 h after exercise. Improvements to IS and glucose tolerance after the OGTT persisted for up to 24 h after HIIE and MIE, but no changes to fasting outcomes were observed over the 48 h period. In contrast to Chapter 5, Chapter 7 reports that a single bout of HIIE but not work-matched MIE resulted in only a small improvement in IS in 8-10 year old boys. Chapter 8 assesses the efficacy of 6 sessions of HIIE performed over 2 weeks to alter fasting and postprandial (mixed-meal tolerance test) insulin and glucose outcomes in adolescent boys. In contrast to acute exercise (Chapters 5 and 6), HIIE training over 2 weeks did not improve insulin and glucose outcomes in this population. Finally, Chapter 9 presents a case study on three adolescents with T1D to examine the effect of acute HIIE and MIE on glycaemic control. This study indicates that both MIE and HIIE have the potential to improve short-term (24 h) glycaemic control within this clinical population. Taken collectively, the studies from this thesis demonstrate that HIIE offers an effectual and feasible alternative to MIE to improve insulin and glucose health outcomes in healthy children and adolescents, and short-term glycaemic control in adolescents with T1D.