Nutritional Effects on Insulin Signaling and Action

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DESCRIPTION (provided by applicant): This proposal seeks to elucidate the mechnaism of insulin resistance in humans, specificially with regard to nutritional (over- and underfeeding) effects on insulin action. In particular, we believe that an imbalance in the expression of the subunits of phosphatidylinositol (PI) 3-kinase represents the earliest biochemical change leading to insulin resistance. PI 3-kinase consists of a regulatory subunit, p85, and a catalytic subunit, p110. Normally, the regulatory subunit exists in excess to the catalytic one. Thus, there exists a balance between the free p85 monomer and the p85-p110 heterodimer with the latter being responsible for PI 3-kinase activity. Increases or decreases in expression of p85 shift this balance in favor of either free p85 or p85-p100 complexes. Because the monomer and the heterodimer compete for the same binding site on the IRS proteins, an imbalance could cause either increased or decreased PI 3-kinase activity. If the expression of p85 can be enhanced nutritionally, the resultant changes in the ratio of p85 to p110 may be the earliest manifestation of ensuing insulin resistance. This can also explain how overfeeding and weight gain trigger insulin resistance. We hypothesize that the expression of p85 in the insulin target tissues of normal individuals can be influenced nutritionally (overfeeding), thus altering the balance between p85 and p110 and leading to reduced PI 3-kinase activity and triggering insulin resistance. Furthermore, nutritional interventions that improve insulin sensitivity (caloric restriction) should lead to a reduction in p85 expression, to a decrease in the ratio of p85 to p110, enhanced PI 3-kinse activity, and improved insulin sensitivity. To explore these hypotheses we will address the following specific aims: Specific Aim 1: To determine the impact of short-term overfeeding and macronutrient composition on expression of PI 3-kinase subunits, their stoichiometry, PI 3-kinase activity, and insulin action in normal individuals. Specific Aim 2: To determine the impact of acute caloric restriction and macronutrient composition on expression of PI 3-kinase subunits, their stoichiometry, PI 3-kinase activity, and insulin action in obese insulin resistant individuals. Specific Aim 3: To determine the impact of long-term hypocaloric intake, macronutrient composition, and weight loss on expression of PI 3-kinase subunits, their stoichiometry, PI 3-kinase activity, and insulin action in obese insulin resistant individuals. Finally, we will also examine the baseline differences in PI3-kinase subunit expression and stoichiometry between normal weight, insulin-sensitive individuals and obese, insulin-resistant individuals. Even though insulin resistance is a well-defined clinical condition, its primary cause remains unknown. Clinically, insulin resistance is a prevalent condition and a cardinal feature of obesity, type 2 diabetes mellitus, hypertension, and the metabolic syndrome. One of the most significant public health consequences of insulin resistance is its frequent association with cardiovascular problems. We believe that we might have some initial clues as to how insulin resistance is being induced. Unraveling the mechanism of insulin resistance would have an enormous impact on the field of diabetes, obesity and metabolic syndrome.