New Technique Opens Novel Approaches to Insulin Resistance
A newly-described technique could open multiple lines of investigation into the pathophysiology and treatment of insulin resistance, with exciting implications for diabetes research.
Insulin Resistance and the Risk of Diabetes
Insulin resistance is one of the major risk factors for prediabetes and type 2 diabetes; however, the exact cause of this resistance is unknown. Contributors are currently thought to include carrying excess weight and physical inactivity.
Insulin resistance occurs when liver, muscle, and fat cells fail to respond correctly to insulin (which they should use to convert glucose to energy). Glucose is therefore less easily absorbed by the cells from the bloodstream, which stimulates the pancreas to produce more insulin. These higher insulin levels help glucose to enter the cells, keeping blood glucose in a “normal”, healthy range.
Eventually, though, pancreatic beta cells fail to supply this increased insulin demand, glucose levels build up in the bloodstream, and prediabetes and diabetes occur.
Understanding Insulin Movement to Potentially Reverse Resistance
A study published recently in the Journal of Clinical Investigation has unveiled a new microscopy technique to better understand insulin movement, which may lead to new ways to reverse insulin resistance and potentially prevent diabetes onset.
To fully understand insulin resistance, and potentially reverse the phenomenon, it’s important to characterize some background details on insulin movement. Before insulin can stimulate muscle cells to take up glucose, the insulin must exit blood vessels by crossing the capillary endothelium and entering the muscle cells.
However, up to now, the exact mechanism of endothelial insulin transport from blood vessels to skeletal muscle cells has been unclear. This is due to a lack of methods to directly measure the rates of molecular efflux across the capillary endothelium in vivo.
The ability to characterize the mechanisms which control how insulin leaves a capillary would be a critical first step to understanding the development and progression of insulin resistance.
Combining Measurement of Microcirculatory Function with Molecular Transport In Vivo
The recent study developed a novel preclinical microscopy technique which combined direct visualization of insulin efflux from capillaries with modeling insulin efflux kinetics in vivo. This quantitative intravital fluorescence microscopy technique, combined with mathematical modeling allowed researchers to follow and model the real-time movement of fluorescently labeled insulin as it crossed capillaries in mice.
Insulin Moves Across the Endothelium by Fluid-Phase Transport
The main finding from this research is that fluid-phase transport is the major mode of transendothelial insulin efflux in mice, which can be achieved by either:
- convective movement of insulin through interendothelial junctions
- a nonspecific vesicular process
- or a combination of the two.
This new finding disproves previously held hypotheses that insulin transport was saturatable, or that it needs an insulin receptor. The authors suggest that the differences from existing study outcomes arise from the differing techniques used; older studies looked at movement across cultured monolayers of endothelial cells, while this new technique examines capillaries in vivo.
Implications for Insulin Resistance and Diabetes Research
Moving forwards, the new data can shed more light on the pathophysiology of insulin resistance and potential strategies for its treatment, such as developing small molecules to enhance insulin delivery.
Beyond diabetes, the new in vivo imaging technique described in this research is applicable to studying how other agents access tissues, hopefully enabling more breakthroughs in a range of therapeutic areas.
- Williams et al. Insulin exits skeletal muscle capillaries by fluid-phase transport. J Clin Invest 2018; 128(2) 699-714.
- Kolka and Bergman. The Endothelium in Diabetes: its role in insulin access and diabetic complications. Rev Endocr Metab Disord 2013; 14(10: 13-19.
- Taylor. Insulin Resistance and Type 2 Diabetes. Diabetes 2012; 61(4): 778-9.