Doctors have made huge advancements in the treatment and diagnosis of diabetes, especially when it comes to reducing premature deaths. But we still haven’t /cured/ it, which means we still have to put some funding and research into the /management/ of the disease. And while there’s a ton of cool biotech to get into with diabetes monitoring devices, today we’re focusing on two chemicals: the hormone insulin, and metformin, a drug that is /not/ a hormone. We’ll start with insulin.
Diabetes has been on medical radar FOREVER. Like even ancient Indian doctors gave it a term that literally means “honey urine” because it attracted ants. The official term diabetes came around in the first century while 17th century scientist Thomas Willis threw the term mellitus on the end to confirm that diabetic urine was indeed sweet tasting. I… okay….use the tools you have I guess. Luckily the 1800s would feature a lot more microscopes than tasting parties. In 1869, Paul Langerhans identified a bunch of clear cells in the pancreas that became known as the islets of Langerhans. He thought these were immune cells, but they weren’t.
These types of cells secrete lots of different hormones. Then in 1889, two scientists, Oskar Minkowski and Joseph von Mering removed the pancreas from a dog and it started urinating a /lot/. And not only was it peeing more, but it’s urine was /12 %/ sugar. They repeated the pancreas removal with a couple more dogs and same thing. These dogs had diabetes. And that’s where hormones really start coming in here.
Minkowski and Mering would take pancreatic tissue, throw it back in the dog, and it would delay on the onset of diabetes. It’s the /same strategy/ Berthold used with the rooster testicles or that Emil Theodor Kocher used with thyroid tissue. Put a bit of endocrine organ in the body and it still pumps out hormones. Fast forward to the 1920s and the medical community is full steam ahead on endocrinology. Remember, hormones had just been discovered a few years prior, so even though doctors didn’t know the answer to everything, they could at least entertain the idea that “mmm, maybe it has to do with hormones” Knowing what we knew about the function of the whole organ AND a little bit more about its physiology now, researchers identified a hormone from the Islets of Langerhan in 1921 and named it insulin after the “islets” or “island” cells it came from.
The very next year, they starting injecting diabetics with insulin and saw some /dramatic/ results. But this kind of insulin was almost an emergency medicine of sorts. It was fast acting only, so patients had to deal with frequent injections. So over the next couple years, we’d get different versions of promethazine zinc insulin which has a much longer release time and is pretty similar to the insulin strategy we have today. Now, I’d argue this is about as magic bullet as it gets for any particular disease. Diabetes is a deficiency or lack of the body’s ability to create insulin, so by artificially giving the hormone your body can’t produce, you fix the problem.
But you probably know that diabetics are also concerned with their diet and exercise, and that doctors will usually advise that diabetics adopt a healthier lifestyle. And it’s true, regular exercise is a big part of the treatment of diabetes, but we’re more likely to rely on a couple prescriptions and blood glucose monitoring than just a gym membership, so why is that? While the discovery of insulin was an enormous moment in diabetes treatment, it didn’t fix everything. So the next place we looked was a couple prescription drugs, and exercise. We knew diabetes was a metabolic problem. A fuel source, glucose, isn’t being used by the cells, and insulin lets that happen.
Exercise would hopefully do the same thing, which makes sense. We need energy to exercise, glucose is a source of energy, so maybe exercise would remove glucose from our blood and we could avoid some of those diabetic complications. And some studies in the early 1900s showed exactly that. Exercise reduced blood glucose concentration and had a synergistic effect when the subject took insulin before exercise. But we also saw the opposite — patients that exercised so much they became hypoglycemic, their blood sugar went too low.
Unfortunately it took us 50 years from the first clinical use of insulin for us to formally study the physiology behind the mechanism and ask like, ya know, “how does this actually work”? A big moment was in 1984 when research published in the American Journal of Physiology showed that muscles in diabetics could use glucose regardless of whether they or not they were on insulin. And that was huge! Previous research hinted that muscles still needed some minimum threshold of insulin to let glucose in, but this research showed the opposite. The research team took a bunch of rats in severe ketoacidosis, then just to be sure, used a chemical mixture that wiped out any extra insulin. The scientists hooked the rats’ hind legs to electrodes and made them contract — simulating exercise, and muscular glucose uptake increased across the board. Now, this was a far cry from exercise “curing” diabetes, but it was still a big discovery! Muscles didn’t need insulin to contract after all. Doctors could prescribe exercise as a way to lower blood sugar in both the short and long term now.
BUT, of course, as behavioral scientists will tell you, It is really really hard to get people to change their exercise habits. As the author Marshall Goldsmith said “Meaningful behavior change might be most difficult thing for sentient beings to accomplish”, so good luck cardiac rehab therapists! So if were a doctor back then, you’re in a bit of a pickle. Insulin is already doing the heavy lifting in your treatment, but you want to do more. So do you prescribe exercise knowing your patient probably isn’t going to do it, or do you look for an another way to supplement your treatment? Luckily in the mid 90s, a drug called metformin was introduced in the US after a kind of sketchy past.
We’d known that this class of drugs, or biguanides, lower blood glucose by preventing the liver from converting fats and amino acids into glucose since roughly the 1920s. But in the 70s, two of metformin’s cousins, buformin and phenformin, were linked to lactic acidosis, so science became less interested in the biguanide drugs, but research picked up again in the 80s and 90s, and by 1995, metformin was available in the United States as a first line of defense against type 2 diabetes. And this was great timing, because by the early 2000s, the percentage of people with diabetes in the US had multiplied many times over in the past 50 years. So if you were a doctor back then, you all of a sudden had a powerful treatment strategy.
You had the old insulin injections to lower blood sugar, metformin to keep a bunch of sugar from coming out of the liver, and exercise as a way to improve insulin sensitivity. But the question remained: the incidence of diabetes is climbing super fast, so how can we prevent it? So in 2002, the medical community was very much listening when a paper published in The New England Journal of Medicine answering that exact question. The study took over 3200 /non-diabetic/ subjects and randomly assigned them a placebo, metformin twice a day, or lifestyle modification including a 7% reduction in body weight and 150 minutes of physical activity per week. That’s 30 minutes of exercise 5 days a week, which is a pretty challenging exercise prescription for people who might not exercise. Remember, these people weren’t diabetic, but they were recruited because they were at increased risk for diabetes, and we wanted to find a prevention strategy.
They had to be adults, because we’re only looking at adult onset, or type 2 diabetes, have a BMI over 24 since obese folks are more likely to develop the condition, and have elevated fasting and post-prandial glucose levels, giving us a hint that insulin might not be working as expected. Going into the study, we already had some data to show that exercise and diet worked, but metformin was the wildcard. It had only been introduced in America a year before the study started, and had only been studied in diabetes treatment, not prevention. But if you know that exercise is gonna be effective, you can’t tell the drug groups not to exercise because ETHICS. So they got /some/ information about healthy exercise and diet, but it wasn’t enforced. On the other hand, the exercise group worked! This group completed /16/ 1-on-1 coaching sessions about healthy eating, exercise, and behavior change that was all designed to be culturally sensitive, flexible, and individualized to the patient.
Like it’s exhausting listening to this, these researchers were not messing around with their exercise prescription. And what’s surprising is the subjects /actually/ followed through. After 24 weeks, half of that group had lost the 7% in body weight, and three quarters of them actually did their assigned exercise. If this were a New Year’s resolution, it would runaway, undoubtedly be the most successful resolution in history. I’m going into so much detail here because, 1, if you want to design a successful behavioral change tudy, take notes to what they did in this study, and 2, it’s results time! Remember, all these participants were at risk of developing diabetes.
The placebo group had the highest rate, 11% of their participants were diagnosed with diabetes, 7.8% in the metformin group, and 4.8% in the lifestyle modification group. But that’s amazing, right! Look at how effective exercise and diet are at preventing diabetes. Like, here’s what they say in the results section. “our study showed that treatment with metformin and modification of lifestyle were two highly effective means of delaying or preventing type 2 diabetes” Waaait a second, that phrasing makes it seem like these two strategies are the same.
Now there’s a chance you’re kind of mad at the outcome of this. Like if exercise is so much more effective at preventing diabetes than drugs, why aren’t we spending more effort promoting exercise, right? Like every way you manipulate these statistics, lifestyle modification is clearly the best choice, this has gotta be a big pharma media manipulation story, right? No dude, it’s way more complicated than that. Take you clinical hat off and put the public health hat on. Diabetes is a /global/ problem. It takes a baseline of privilege to implement the intense lifestyle change they did in the study, and if we want to do the most good to the most amount of people, we have to use the tools available. Generic metformin is cheap.
Waaaay cheaper than eventually being put on insulin. So if health care providers can help with frequent screenings and cheap, effective drugs, we have to. And I wanted to tell the metformin story because of that. You’re not going to get everyone to exercise 30 minutes a day — it’s /amazing/ that the 2002 study did — but if metformin helps, it helps. Whether we’re teachers, clinicians, or even dating someone, the key to communication change is meeting people where they’re at.
This video was a collaboration with my friend Willie’s channel, Khanubis which you can find right here. He put a video together about the last 100 years of medicine which is totally worth checking out right here. Also, I just wanted to say thank you. It’s been 10 months since I rebranded the channel to Corporis and I’m really happy with how things are going lately. Have fun, be good. Thanks for watching.
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Source: Corporis
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