archives@tulane.edu / Androgen excess predisposes females to type 2 diabetes. Using mouse models, our lab reported that androgen excess causes insulin resistance via activation of the androgen receptor (AR) in the brain. Neurons of the arcuate nucleus of the hypothalamus (ARC) regulate hepatic glucose production (HGP). Thus, I hypothesized that in female mice, androgen excess in neurons of the ARC causes hepatic insulin resistance by increasing HGP. To test this, I injected AaV-Cre-GFP or AaV-GFP into the ARC of ARlox/lox female mice to generate ARC-specific AR knockout (ARC-ARKO) and control mice, respectively. When exposed to a Western diet, control female mice chronically treated with dihydrotestosterone (DHT) developed insulin resistance and fasting hyperglycemia compared to vehicle-treated control mice. In contrast, DHT-treated ARC-ARKO mice remained insulin sensitive and normoglycemic compared to vehicle-treated ARC-ARKO mice. During a hyperinsulinemic-euglycemic clamp, insulin’s ability to suppress HGP was blunted in DHT-treated control mice. In contrast, insulin was still able to suppress HGP in DHT-treated ARC-ARKO females. Additionally, during the clamp, DHT-treated control mice showed no alteration in hepatic activation of AKT, a marker of hepatocyte insulin sensitivity, but exhibited reduced activation of hepatic STAT3, a marker of hypothalamic insulin sensitivity. In contrast, in DHT-treated ARC-ARKO mice activation of hepatic STAT3 was increased. In a parallel study, estradiol treatment improved insulin sensitivity in control ovariectomized (OVX) mice. In contrast, in DHT-treated OVX mice, estradiol treatment did not improve insulin sensitivity. Together these results suggest that in female mice exposed to a Western diet, androgen excess causes hypothalamic estrogen resistance and insulin resistance in ARC neurons via action at the AR leading to impairments in the brain-IL6-pSTAT3 pathway which results in unsuppressed HGP. / 1 / Jamie Morford

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第13062号 / 論医博第2120号 / 新制||医||1018(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 長船 健二, 教授 川口 義弥, 教授 松田 道行 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

M.Sc. (Med.), Faculty of Health Sciences, University of the Witwatersrand, 2009

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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Alzheimer’s Disease is a particularly vicious illness, with currently no preventative or curative treatment available. This paper focuses on how impairments in glucose metabolism and insulin signaling contribute to the disease process and further, on potential treatment options that target these specific dysfunctional processes in hopes of finding an effective cure or prevention therapy. Glucose hypometabolism presents years prior to the clinical symptoms of Alzheimer’s Disease and promotes the accumulation of Aβ, oxidative stress, and mitochondrial dysfunction. Addition-ally, a downregulation of GLUTs, particularly GLUT1 and GLUT3 also serves to de-crease neural glucose uptake as well as to escalate glucose hypometabolism. More-over, insulin resistance promotes tau hyperphosphorylation and extracellular ag-gregation of Aβ42, contributing to the Alzheimer’s Disease pathology. Due to the central role of insulin and glucose neural dysfunction to Alzheimer’s Disease, these processes pose as strong potential targets for much-needed Alzheimer’s Disease curative and preventative therapy. Specifically, antioxidants and antidiabetics such as Metformin, thiazolidinediones, sulfonylureas, incretins, and intranasal insulin have shown some potential as future treatment options for Alzheimer’s Disease but require further investigation. Some non-pharmacological approaches, such as the ketogenic diet, have also been proposed as viable treatment options and work via their effects on glucose and insulin pathways. Dysfunctional glucose metabolism and insulin resistance are incredibly important in the progression of the Alz-heimer’s Disease stages and as such, present as viable potential targets of future drug therapies.

Calcium/calmodulin-dependent protein kinase II (CaM kinase II) is demonstrated to exist in the ß-cell and immunopecipitation. Glucose and potassium significantly stimulate the rapid autophosphorylation of CaM kinase II and proportionally induce autonomous activity of the kinase in a dose-dependent manner that parallels insulin secretion. The activation of CaM kinase II, alloxan, KN-62 and KN-93, suggest that the enzyme is an integral component of insulin secretion and/or related processes in the β-cell.

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).

The study utilizes the yeast two-hybrid system to try and unravel the molecular link between the G protein-coupled receptors (GPCR) and the receptor tyrosine kinases (RTK). The fourth melanocortin receptor (MC4R) and the angiotensin receptor AT1 are both GPCRs while the insulin receptor (IR) and the epidermal growth factor receptor subtype-2 (ErbB2) belong to the RTK family. Alteration in the functioning of MC4R receptor can cause obesity. Development of insulin resistance and diabetes is a risk factor associated with obesity. Overexpression of the ErbB2 receptor is seen in a number of breast cancers. The interaction between the AT1 and ErbB2 receptors were studied based on previous studies that have shown an interaction between the epidermal and angiotensin receptors. Thus, Interactions between the MC4R and the IR, and that between the AT1 and ErbB2 receptors were studied for their possible roles in metabolic syndrome and cancer.

No description available.