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MICROMouse Program Application Abstract

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Metabolic Fluxes During Hyperinsulinemic Euglycemia in Insulin Resistant Mice

Nishanth Sunny (Dallas, TX)

MICROMouse Program

Insulin resistance (IR) and the accompanying defects in insulin signaling negatively impacts nutrient partitioning resulting in abnormal glucose metabolism and higher rates of lipid synthesis and accumulation in the liver and muscle. Defects in pathways of fat oxidation and subsequent accumulation of byproducts of incomplete fat oxidation, ceramides and diacylglycrol have been proposed as a potential mechanism which initiates the cascade of insulin signaling defects and subsequent metabolic alterations. However, the causal defects in fat oxidation pathways, thought to be responsible for the accumulation of these byproducts have not been well documented, particularly in the liver. Further, interconnectivity of metabolic pathways allows shuttling of carbon units between multiple pathway networks; thus alterations in urea and protein metabolism occur side by side with changes in fat metabolism in various models of IR. The severity of the inherent defects in cytoplasmic and mitochondrial pathways often depends on the stage of IR (e.g. prediabetes vs diabetes) or the characteristics of the animal model (e.g. diet induced vs genetic), and thus these defects need not always clearly manifest under basal experimental conditions. When IR was induced by 8 wks of high fat feeding in mice, it did not accompany any alterations in glucose, TCA cycle and fat metabolism. The overall goal of this proposal is to couple stable isotope based metabolic flux analysis by NMR and mass spectrometry to a hyperinsulinemic euglycemic clamp protocol to quantify multiple central metabolic pathways. We will test the hypothesis that subtle defects in nutrient fluxes, especially in the liver which accompany IR but precede frank diabetes will manifest under the hormonal action of insulin. We will utilize the 8 wk high fat (60% fat calories) fed mice model of IR to quantify nutrient flux rates through pathways of glucose, amino acid and fat metabolism.The proposed method will allow investigators to profile multiple metabolic flux alterations under hyperinsulinemic euglycemia in various diet induced or genetic mice models.

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