Opening of the mitochondrial permeability transition pore links mitochondrial dysfunction to insulin resistance in skeletal muscle.

Insulin resistance is associated with mitochondrial dysfunction, but the mechanism by which mitochondria inhibit insulin-stimulated glucose uptake into the cytoplasm is unclear. The mitochondrial permeability transition pore (mPTP) is a protein complex that facilitates the exchange of molecules between the mitochondrial matrix and cytoplasm, and opening of the mPTP occurs in response to physiological stressors that are associated with insulin resistance. In this study, we investigated whether mPTP opening provides a link between mitochondrial dysfunction and insulin resistance by inhibiting the mPTP gatekeeper protein cyclophilin D (CypD) in vivo and in vitro. Mice lacking CypD were protected from high fat diet-induced glucose intolerance due to increased glucose uptake in skeletal muscle. The mitochondria in CypD knockout muscle were resistant to diet-induced swelling and had improved calcium retention capacity compared to controls; however, no changes were observed in muscle oxidative damage, insulin signaling, lipotoxic lipid accumulation or mitochondrial bioenergetics. In vitro, we tested 4 models of insulin resistance that are linked to mitochondrial dysfunction in cultured skeletal muscle cells including antimycin A, C2-ceramide, ferutinin, and palmitate. In all models, we observed that pharmacological inhibition of mPTP opening with the CypD inhibitor cyclosporin A was sufficient to prevent insulin resistance at the level of insulin-stimulated GLUT4 translocation to the plasma membrane. The protective effects of mPTP inhibition on insulin sensitivity were associated with improved mitochondrial calcium retention capacity but did not involve changes in insulin signaling both in vitro and in vivo. In sum, these data place the mPTP at a critical intersection between alterations in mitochondrial function and insulin resistance in skeletal muscle.

Interruption to research design: substance driven research.

When adolescent women, readers of YM, Seventeen, and Teen, met individually and in a series of four or five focus group meetings to talk about the health messages in teen magazines, their surprising responses did not fit the feminist, critical theory, and media reception analysis methods used to guide the study. The undisputed acceptance of research methods as the sole means to knowledge and truth was interrupted by the voices of the adolescents that resisted methodological codification. Hermeneutics or interpretive inquiry transformed my study to one that became substantively driven and contributes to the qualitative approaches in the human sciences.

Wanna know a secret?

In a study to examine adolescent perceptions of popular teen magazines, two focus groups of adolescent women met four or five times as groups and individually to discuss the health messages in the images and texts they chose from popular teen magazines. They noted that many of the messages in teen magazines are couched in terms of secrets. Interpretive inquiry created an understanding of certain facets of secrets and secrecy as they pertain to popular teen magazines and the adolescent women who read them. Secrets revealed themselves through their links with other secrets in the lifeworld. This interpretive work is an example of substantively driven research where the power of the topic takes the lead guiding the development of knowledge surrounding secrets.