Abstract: Insulin injected directly into skeletal muscle diffuses rapidly through the interstitial space to cause glucose uptake, but this is blocked in insulin resistance. As glucotoxicity is associated with endothelial dysfunction, the observed hyperglycemia in diet-induced obese dogs may inhibit insulin access to muscle cells, and exacerbate insulin resistance. Here we asked whether interstitial insulin diffusion is reduced in modest hyperglycemia, similar to that induced by a high fat diet.
Methods: During normoglycemic (100 mg/dl) and moderately hyperglycemic (120 mg/dl) clamps in anesthetized canines, sequential doses of insulin were injected into the vastus medialis of one hindlimb; the contra-lateral limb served as a control. Plasma samples were collected and analyzed for insulin content. Lymph vessels of the hind leg were also catheterized, and lymph samples were analyzed as an indicator of interstitial insulin concentration.
Results: Insulin injection increased lymph insulin in normoglycemic animals, but not in hyperglycemic animals. Muscle glucose uptake was elevated in response to hyperglycemia, however the insulin-mediated glucose uptake in normoglycemic controls was not observed in hyperglycemia. Modest hyperglycemia prevented intra-muscularly injected insulin from diffusing through the interstitial space reduced insulin-mediated glucose uptake.
Conclusion: Hyperglycemia prevents the appearance of injected insulin in the interstitial space, thus reducing insulin action on skeletal muscle cells.
Alex’s Notes: Insulin (and all hormones for that matter) must reach a cell to exert its effects. Insulin does not do anything while circulating around in the blood, and instead it must bind to insulin receptors on the surface of target cell membranes. Insulin transport from the pancreas and capillaries to the interstitial space is the rate-limiting step for insulin signaling, and as it turns out, this bottle neck step is impaired during insulin resistance.
Previous works by the authors have demonstrated that both lipid infusion and high-fat feeding induce insulin resistance and prevent insulin from reaching the interstitial fluid. This in turn prevents the insulin-dependent glucose uptake into skeletal muscle. However, a critical difference between the two methods is that the high-fat feeding does not elevate blood lipids during the actual study of insulin, leaving the factor that prevents insulin signaling unknown. However, high-fat feeding did result in elevated fasting blood glucose levels, leading to the basis of the current study.
Fifteen dogs were divided into two groups for testing: those maintained at normoglycemic levels (control), and those maintained at hyperglycemic levels (120 mg/dL). During the morning of the experiment, the animals were fasted for 15 hours and had insulin injected every hour for 4 hours into one hind-limb only while under a basal insulin euglycemic clamp. This allowed the researchers to measure insulin sensitivity and glucose uptake of both the injected muscle as well as the peripheral muscles (in this case, the non-injected hind-limb).
The hyperglycemic group had a significantly higher plasma glucose concentration, as determined by the study design (120 vs ~95 mg/dL). After each insulin injection, arterial and vein insulin concentrations in the injected leg increased significantly, with no differences between the normo- and hyperglycemic groups. However, the normoglycemic group also showed a rise in lymph insulin concentrations while the hyperglycemic group did not; indicating that insulin in this group was not reaching the cell. In support of this, the normoglycemic group has a significant increase in glucose uptake in both legs after insulin injection when compared to the basal time point, but the hyperglycemic group had no significant glucose uptake upon insulin injection.
“Here we show that even modest hyperglycemia can impair the dispersion of injected insulin through the interstitial space. While intramuscularly injected insulin enters the vein at the same rate in control and hyperglycemia, access of insulin to the interstitium (indicated by our lymph measurements) was impaired by modestly elevated plasma glucose suggesting that the injected insulin is unable to access the cell surface and is thus unable to initiate insulin-mediated glucose uptake.”
Interestingly, a study in obese women also demonstrates that postprandial hyperglycemia have impaired delivery of insulin to both adipose tissue and skeletal muscle.
But 120 mg/dL is way below a healthy person’s postprandial level!
Yes it is, but we also must remember that this experiment induced a more prolonged hyperglycemia (~6 hours) than would be expected to occur after eating. Thus, this glucose concentration is more akin to that seen in persons with diabetes or metabolic syndrome. That said, six hours is still a very short timeframe for elevated blood glucose levels to induce insulin resistance.
Can we do this with diet?
This study raises an interesting point about meals and their macronutrient combinations. I had previously written about how adding butter to a potato results in a greater insulin response to handle the incoming glucose. But why would this be? Consider the following.
The glucose from the starch attempts to enter the muscle and adipose tissue. As it does so, it (or more accurately, insulin) inhibits lipolysis so that serum free fatty acid levels are reduced. If these levels were not reduced, then they would enter muscle tissue and inhibit glucose uptake/oxidation. But eating fat also has this outcome. Therefore, eating fat + carbohydrate causes excessive hyperglycemia and fat storage because the glucose cannot enter the muscle (responsible for about 80% of glucose uptake by the way) and instead heads to adipose tissue to continue inhibiting fat oxidation. Therefore, when consuming a high-fat, high-carbohydrate meal, it is possible that the numerous negative feedback and allosteric inhibitory loops within the body cause a state of “chaos” that result in our cells starving in abundance. It doesn’t matter if this is a buttered potato or French fries.
On this note, many people believe that they are doing their body good by consuming their starches with fats to lower the glycemic response. But without getting into the faults of that, it must be acknowledged that there are other consequences to this food combination.