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This document only includes an excerpt of the corresponding thesis or dissertation. To request a digital scan of the full text, please contact the Ruth Lilly Medical Library's Interlibrary Loan Department (rlmlill@iu.edu).

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This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. / Objective: This study was undertaken to evaluate the association between components defining insulin resistance and breast cancer in women. Study Design: We conducted a systematic review of four databases (PubMed-Medline, EMBASE, Web of Science, and Scopus) for observational studies evaluating components defining insulin resistance in women with and without breast cancer. A meta-analysis of the association between insulin resistance components and breast cancer was performed using random effects models. Results: Twenty-two studies (n = 33,405) were selected. Fasting insulin levels were not different between women with and without breast cancer (standardized mean difference, SMD 20.03, 95%CI 20.32 to 0.27; p = 0.9). Similarly, non-fasting/ fasting C-peptide levels were not different between the two groups (mean difference, MD 0.07, 20.21 to 0.34; p = 0.6). Using individual odds ratios (ORs) adjusted at least for age, there was no higher risk of breast cancer when upper quartiles were compared with the lowest quartile (Q1) of fasting insulin levels (OR Q2 vs. Q1 0.96, 0.71 to 1.28; OR Q3 vs. Q1 1.22, 0.91 to 1.64; OR Q4 vs. Q1 0.98, 0.70 to 1.38). Likewise, there were no differences for quartiles of non-fasting/fasting C-peptide levels (OR Q2 vs. Q1 1.12, 0.91 to 1.37; OR Q3 vs. Q1 1.20, 0.91 to 1.59; OR Q4 vs. Q1 1.40, 1.03 to 1.92). Homeostatic model assessment (HOMAIR) levels in breast cancer patients were significantly higher than in people without breast cancer (MD 0.22, 0.13 to 0.31, p, 0.00001). Conclusions: Higher levels of fasting insulin or non-fasting/fasting C-peptide are not associated with breast cancer in women. HOMA-IR levels are slightly higher in women with breast cancer.

Insulin resistance is the major metabolic defect in obesity and Type 2 diabetes. Increased lipid accumulation is strongly associated with insulin resistance. A significant component of insulin resistance is thought to be a reduced ability of insulin to activate the cascade of phosphorylation events that lead to the metabolic effects of this hormone. The broad aims of this thesis were to examine the effect of high-fat diets containing different fat subtypes on in vivo insulin signalling, under conditions normally used to detect whole body insulin resistance, and to compare the effects of acute and chronic lipid oversupply on insulin signalling in vivo. Time-course and dose-response effects of insulin stimulation on site-specific phosphorylation of key signalling proteins were studied in rat tissues in vivo, to establish an appropriate experimental system to examine the onset of activation of the insulin signalling pathway. It was determined that short insulin infusions with concurrent glucose infusion, similar to the beginning of a euglycaemic-hyperinsulinaemic clamp, significantly increased the phosphorylation of major intermediates of the insulin signalling pathway in important tissues of insulin action (skeletal muscle [RQ], liver [LIV] and white adipose tissue [EPI]). These experiments provided a platform to study insulin signalling under the same conditions used to study lipid-induced insulin resistance. The provision of diets enriched in polyunsaturated or saturated fatty acids (FA) resulted in the corresponding enrichment of these fat subtypes in rat plasma and tissues. However, the effects on insulin signalling were essentially the same. Both fat diets induced defects in sitespecific phosphorylation of insulin receptor substrate (IRS)-1 and protein kinase B (PKB) in RQ and LIV, but not EPI. This suggests that the amount of fat in the diet, rather than enrichment in a particular fat subtype, had a greater impact on the development of signalling defects and that the response to high-fat feeding was tissue-specific. A 3hr elevation of circulating FA (using a lipid/heparin infusion), to a level that is relevant in clinical Type 2 diabetes, impaired insulin-stimulated PKB phosphorylation with no significant effect on IRS-1 phosphorylation. This suggests that there may be differences in the way acute and chronic exposure to increased FA impair insulin signalling. The phosphorylation defects observed in both chronic and acute studies did not seem to be associated with activation of major stress signalling pathways (JNK and NFkB), which have been suggested to have a role in lipidinduced insulin resistance. In conclusion, these studies demonstrate that impaired IRS-1 and PKB phosphorylation do have a role in the reduced insulin action observed with lipid oversupply in vivo, because the changes were detected under similar conditions as those used to determine whole body insulin resistance.

The Ser/Thr kinase Akt plays an important role in many of insulin's actions including GLUT4 translocation to the plasma membrane (PM). However, there are several features of Akt's regulation of GLUT4 translocation that remain unclear. The goal of my thesis was to resolve some of the following questions: Is activation of Akt sufficient to stimulate GLUT4 translocation? What is the quantitative relationship in signal transmission between individual components within the Akt cascade? What is the role of Akt in insulin resistance? To determine if activation of Akt is sufficient to mediate GLUT4 translocation, I developed a drug-inducible heterodimerisation strategy to activate Akt2 independently of other potential insulin signalling pathways. These studies revealed that activation of Akt2 resulted in rapid stimulation of GLUT4 translocation to a similar extent with maximum insulin, indicating that Akt2 is sufficient for this event. It was previously observed that maximum effect of insulin on GLUT4 translocation was obtained with minimum activation of Akt. To resolve this discrepancy, the relationship between Akt signalling components was examined using a quantitative kinetic and dose response approach combined with hierarchical cluster analysis. Most notably I observed a strong relationship between Akt at the PM, but not Akt in the whole cell lysate, with its substrate phosphorylation. Active pools of phospho-Akt and -AS160, a major substrate involved in GLUT4 translocation, were found in the lipid raft, highlighting the importance of subcellular partitioning of key signalling components for achieving biological specificity. The involvement of Akt in insulin resistance was investigated using the heterodimerisation strategy. These studies revealed that insulin itself initiates a pathway that causes insulin resistance by converging on target(s) downstream of Akt. This inhibitory pathway emanates from PI3-kinase and is likely induced by a range of insults including chronic insulin and dexamethasone. In conclusion, Akt is a crucial element in the insulin action pathway that exhibits precise spatial regulation. While the role of this nanoregulation of Akt in disease remains to be evaluated, my studies suggest that the major defect contributing to insulin resistance occurs downstream of Akt. The elucidation of this target will have major implications for metabolic diseases.

Thesis (M.S. )--University of Tennessee Health Science Center, 2008 / Title from title page screen (viewed on July 30, 2008). Research advisor: Atul J. Shukla, Ph.D. Document formatted into pages (xii,119 p. : ill.). Vita. Abstract. Includes bibliographical references (p. 97-119).

Thesis (doctoral)--Lund University, 1989. / Added t.p. with thesis statement inserted.