Putting diabetes in reverse

NASHVILLE, Tenn.—Whereas type 1 diabetes results from a lack of ability to produce insulin (or a vastly diminished ability), usually strikes early in life and is a near-lifelong management problem, type 2 diabetes (T2D) is a different beast. The “diabetes” part might be shared, but T2D often strikes in adulthood and is frequently related to other co-morbidities, such as obesity and lifestyle choices. A hallmark of T2D is insulin resistance.

Now, researchers at Vanderbilt University have gained new insight into insulin resistance—and possibly new avenues for reversing it—by discovering how insulin crosses the capillary endothelium to exit blood vessels and stimulate skeletal muscle cells. They published their results early this year in the Journal of Clinical Investigation.

The team used a novel fluorescence microscopy technique and, in so doing, were able to measure insulin movement across the endothelial wall of skeletal muscle capillaries in the mouse. The microscopy technique developed for these studies, the researchers note, could also be applied to other drugs and hormones to study molecular access to a range of tissues.

“The muscle capillary wall is a formidable barrier to insulin’s action on muscles,” said Dr. David Wasserman, the Annie Mary Lyle Professor of Molecular Physiology and Biophysics at Vanderbilt and director of the Vanderbilt-NIH Mouse Metabolic Phenotyping Center. “It is the rate-limiting step for muscle insulin action and a potential site of regulation. Defining how insulin leaves the capillary is essential to understanding and treating insulin resistance.”

The paper’s lead author, Ian Williams—a graduate student in Wasserman’s lab—made the advancements necessary to measure aspects of microcirculatory function simultaneously with molecular transport in live mice.

One of insulin’s key functions is to stimulate glucose uptake by muscle, where it is stored or used as fuel, but in order to stimulate glucose uptake insulin must cross the endothelial barrier into muscle tissue. Impaired delivery of insulin into tissue is a key feature of insulin resistance and thus T2D. But it wasn’t truly understood how insulin gets from blood vessels to the muscle cells before the Vanderbilt team used the new quantitative intravital fluorescence microscopy technique and combined it with mathematical modeling, demonstrating that insulin moves across the endothelium by fluid-phase transport.

“Such movement is not dependent on the presence of endothelial insulin receptors or limited by saturation of endothelial transport processes, as had been hypothesized previously,” according to the university.

Better understanding of the variables controlling insulin movement across the endothelial wall could lead to improved strategies for reversing insulin resistance, including development of small molecules that enhance insulin delivery or novel insulin analogs that can access muscle more easily, according to the researchers.