You do not come off of insulin therapy.
It’s kind of a rule.
Diabetes does not come with vacations. You can’t forget your insulin and be okay, and the lifestyle of a person with diabetes is a never-ending series of “Why can’t I eat that?”
Sure, gestational diabetes is the exception, but almost half of those cases result in a diabetes diagnosis later. [1] I’ve also seen one patient who changed so radically that he was able to stop taking metformin. But insulin? Once people get insulin dependent diabetes mellitus (IDDM), they’re on it like the do not fly list.
As many of you did, I got into pharmacy to help people. I don’t like that I can’t fix a condition, and just end up managing expectations and the inevitable slide. Plus, there are complications like diabetic ulcers, end organ damage, loss of quality of life…
Does any of this make you ask why?
It made me ask. And hey, at work, I was surrounded by smart people—several of which have doctorates. When I asked my fellow colleagues why the patients’ endogenous insulin wasn’t working, I usually was faced with blank stares.
Some would answer “Beta cell burnout?” and others would suggest that the cells themselves were resistant to insulin, suffering their own version of burnout. They hadn’t thought too much on it, mostly because they were busy doing their job, trying to get patients to take their medication to keep them alive and out of the hospital as much as possible. Yeah, it’s a huge job, and I’m sure a lot of us are sick of just running numbers.
Patients grasp numbers because they can understand them. No one told them why diet and exercise are important, or how hard they have to work, to get back to where they were. Lifestyle modifications tend to fail when it’s treated like a nominal variable rather than a qualitative variable.
It’s not just about the numbers. (YES, follow your algorithms. They’re there for a reason, and we have evidence that they work. They keep the patients as stable as possible. What I’m about to dive into is the WHY of the therapy.)
Most patients think that as long as they count calories, and those numbers are crunched right, their blood sugar is stable and they won’t get any worse. And to be fair, that’s kind of the message we pump out to our clients. “Your blood sugar is high because the sugar can’t get into your cells where you need it. We’re giving you this drug because it helps your body not make more glucose than you need/ because it makes your pancreas make more insulin to get the sugar where it needs to go/ because we need your insulin to be more effective.” And diet and exercise.
And the ‘diet and exercise’ part is usually where I get the eye-roll. It’s the requisite add-on for counseling that nobody really gets into unless you’re a dietician. It’s more or less “Don’t eat simple carbohydrates.”
Here is what you need to know on the WHY.
Insulin and glucose receptors (GLUT4 being my focus today) are hugely involved in cellular signaling! [2] It’s far more complex than the lock-and-key analogy we give patients, but effectively, the number of receptors is dynamic. They can be increased by upregulation [2] (like what good exercise causes) and reduced by downregulation [3] [4] (which is what happens in diabetes).
To help your patients understand better, here’s a new analogy.
Think of the cell like a microscopic house. If the insulin receptor is the doorbell, insulin (like a delivery person) rings the bell, and the GLUT-4 receptor comes to the cell surface to answer the door. [5] In comes glucose, and insulin either goes its merry way or gets brought into the cell too. [5]
If the doorbell is rung too many times, though, the doorbell gets disconnected; the cell makes fewer GLUT4 receptors, or decreases the insulin receptors, or degrades one or both of them. [3] There can be insulin out there in circulation, there can be glucose galore, but not enough receptors come to the cell surface to answer.
It’s the contraction of the muscle cell that pushes GLUT4 receptors up like a miniature lava lamp to let the glucose molecules in (Ever wonder why comatose patients need insulin in their IVs? That would be part of the reason… makes you wonder if a tens machine would help them, right? But that’s another article.). [5] The GLUT4 receptor is wired, literally [6]; in muscle tissue, while it’s normally resting in a vesicle nearby, it is brought to the cell surface by contraction of the muscles. [5]
If you give insulin, you’re sticking your finger on the doorbell and keep ringing it until someone somehow answers. So now, you have a grumpy cell that doesn’t want to open the door, you have a ton of insulin trying to deliver meals of glucose, a cell that’s starving and ordering more delivery but would rather ignore the (doorbell) insulin than let in its food…
Patients are fighting an uphill battle.
So, how do we make their cells more responsive to the insulin they already have?
They have to exercise. Like, short of breath, not just walking but huffing and puffing, truly exerting themselves exercise. [7] It’s going to hurt and be sweaty and messy. Their cells will be screaming and cranky because they are answering an insulin doorbell they don’t want to hear. They will ache and be frustrated, and it is like Sisyphus rolling that boulder uphill. The patients are trying to convince a grumpy and hungry cell (or rather several billion of them) that it must reconnect its insulin doorbell while it’s still hungry.
But it CAN be done, if they have the will power.
And, of course, stop eating sugar. And diet. And exercise. And follow your algorithms.
About the Author: Shelene is a clinical pharmacist with 9 years of pharmacy experience, and certifications that include MTM, travel health, immunization, TB testing, and more. A believer in lifelong learning, Shelene is also studying for her BCGP. She enjoys solving therapeutic puzzles to help patients, and believes in making a difference where she can.
Works Cited
[1] CDC, “Center for disease control,” 30 may 2019. [Online]. Available: https://www.cdc.gov/diabetes/basics/gestational.html. [Accessed 05 august 2021].
[2] a. M. H. Erik A. Richter, “Exercise, GLUT4, and Skeletal Muscle Glucose Uptake,” Physiological Reviews, vol. 93, no. 3, pp. 993-1017, 2013.
[3] Y. N. I. K. a. H. S. Jinhui Ma, “Prolonged Insulin Stimulation Down-regulates GLUT4 through Oxidative Stress-mediated Retromer Inhibition by a Protein Kinase CK2-dependent Mechanism in 3T3-L1 Adipocytes*,” Journal of Biological Chemistry, vol. 289, no. 1, pp. 133-142, January 2014.
[4] F. K. C. K. M Kasuga, “Insulin stimulates the phosphorylation of the 95,000-dalton subunit of its own receptor,” Science, vol. 215, no. 4529, pp. 185-187, 1982.
[5] N. C. f. B. Information, “Translocation of SLC2A4 (GLUT4) to the plasma membrane,” [Online]. Available: https://pubchem.ncbi.nlm.nih.gov/pathway/Reactome:R-HSA-1445148.
[6] H. R. E.Lienhard, “A potential link between insulin signaling and GLUT4 translocation: Association of Rab10-GTP with the exocyst subunit Exoc6/6b,” Biochemical and Biophysical Research Communications, pp. 601-605, 25 september 2015.
[7] B. D. L. K. M. J. B. G. Thomas C, “Effects of acute and chronic exercise on sarcolemmal MCT1 and MCT4 contents in human skeletal muscles: current,” 19 Julyl 2017. [Online]. Available: https://hal-insep.archives-ouvertes.fr/hal-01565188/document. [Accessed 05 august 2021].
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