Doctor of Philosophy / Department of Anatomy and Physiology / Thomas J. Barstow / The overall aims of this dissertation are to determine the incidence and magnitude of insulin resistance (IR) in a cohort of normoglycemic college-age subjects with a family history of type 2 diabetes, and to ascertain if there is early macro- and microvascular dysfunction relative to IR. Study 1 (Chapter 2) revealed a 7-fold range in IR in healthy college subjects concomitant with measures of insulin, both fasted and during an oral glucose tolerance test, but not related with any measure of plasma glucose. These results emphasize that early in the etiology of carbohydrate dysregulation, abnormalities first occur with regard to insulin sensitivity. Using brachial artery blood flow (BABF, Doppler fluxometry) and near-infrared spectroscopy (NIRS) (Chapter 3) we extended the understanding of the use of these non-invasive tools to assess forearm resting metabolic rate and to compare the parameters of both the NIRS oxy-hemoglobin signal, as a index of perfusion in the microcirculation, and BABF, as an independent measure of microvascular reactivity during post occlusive reactive hyperemia (PORH). Resting metabolic rate ranged ~ 2 fold (2.83-5.15 [Mu]MO[subscript2]/min/100g) similar to direct measures. Amplitude, but not kinetic parameters for NIRS variables correlated with comparable parameters for BABF, providing evidence for the possible utility of NIRS in examining microvascular reactivity. In study 3 (Chapter 4), utilizing our extended understanding of hemodynamics garnered from the results of study 2, we assessed the influence of IR on macro- and microvascular reactivity. We observed that i) the magnitude of IR was significantly correlated with attenuation of endothelium-dependent vasodilation of the brachial artery (P< .01) indicating the possibility of a reduced nitric oxide bioavailability and an enhanced atherogenic milieu. Additionally we found ii) BABF at rest and during reactive hyperemia to be strongly correlated with conductance (reduced downstream resistance—an indicator of microvascular control abnormalities) independent of forearm metabolic rate, and iii) parameters of BABF (microvascular response) were also strongly correlated with brachial artery vasoreactivity (macrovascular response). In conclusion, this body of work furthers our insight into the need for earlier identification of "disease" earlier in the progression to type 2 diabetes, and provides direction for future investigations into prevention / intervention to improve microvessel functionality and to slow the atherosclerotic process in larger vessels.

<p>Current evidence suggests that both prediabetes and diabetes can reverse to normoglycemia; however, predictors of remission of these conditions are poorly understood. We performed analyses on 1,209 people with impaired fasting glucose and/or impaired glucose tolerance treated with placebo rosiglitazone and placebo ramipril in the DREAM trial. Normoglycemia was defined as a fasting plasma glucose <5.6 mmol/L and 2-hour plasma glucose <7.8 mmol/L on a 75 g oral glucose tolerance test (OGTT).</p> <p>The effects of baseline ALT and waist to hip ratio (WHR) on regression of prediabetes to normoglycemia 2 years later were found to be interdependent (p-value for interaction 0.01). Adjusted odds ratios ORs (95% CI) of regression to normoglycemia per 10 U/L increase in ALT were 0.79 (0.66-0.94) when WHR was at the mean minus 1 standard deviation (SD), 0.90 (0.80-1.02) when WHR was at the mean of 0.91, and 1.03 (0.90-1.18) when WHR was at the mean plus 1 SD. Adjusted ORs of regression to normoglycemia per 0.1 unit increase in WHR were 0.75 (0.60-0.95) when ALT was at the mean minus 1 SD, 0.91 (0.76-1.08) when ALT was at the mean of 25 U/L, and 1.09 (0.89-1.35) when ALT was at the mean plus 1 SD.</p> <p>Similarly, the effects of baseline ALT and WHR on AUC_{glucose0-120 min} obtained from the OGTT were found to be interdependent (p-value for interaction 0.056). A 10 U/L increase in ALT was associated with an adjusted AUC_{glucose0-120 min} increase of 19.5 (95% CI 5.3 to 33.7) min*mmol/L when WHR was at the mean minus 1 SD, 11.0 (1.4 to 20.6) min*mmol/L when WHR was at the mean of 0.91, and 2.5 (-9.2 to 14.1) min*mmol/L when WHR was at the mean plus 1 SD. A 0.1 unit increase in WHR was associated with an adjusted AUC_{glucose0-120 min} increase of 30.3 (10.2 to 50.3) min*mmol/L when ALT was at the mean minus 1 SD, 18.3 (3.8-32.9) min*mmol/L when ALT was at the mean of 25 U/L, and 6.4 (-11.5 to 24.3) min*mmol/L when ALT was at the mean plus 1 SD.</p> <p>In conclusion, high baseline ALT and WHR predict a lower likelihood of regression of prediabetes to normoglycemia and an increase in AUC_{glucose0-120 min} 2 years later; however, the effects of ALT and WHR on these outcomes are interdependent.</p> / Master of Science (MSc)