WEBVTT 00:00:00.000 --> 00:00:03.200 You know, it's pretty wild when you think about 00:00:03.200 --> 00:00:05.040 it. Insulin, we hear the word all the time, but 00:00:05.040 --> 00:00:08.640 it's story. Even finding versions in things like 00:00:08.640 --> 00:00:11.460 cone snails, using it as a weapon. Yeah, it's 00:00:11.460 --> 00:00:13.439 amazing. It's like chemical warfare for snails. 00:00:13.839 --> 00:00:17.120 And it really challenged those early assumptions 00:00:17.120 --> 00:00:20.329 that... Hormones would all be these tiny molecules. 00:00:20.489 --> 00:00:22.929 Insulin's quite large, relatively speaking. A 00:00:22.929 --> 00:00:26.350 big protein doing this fundamental job. It highlights 00:00:26.350 --> 00:00:28.629 just how, well, how deep its biological roots 00:00:28.629 --> 00:00:31.199 go. Yeah, exactly. That cone snail example. It 00:00:31.199 --> 00:00:33.500 just drives home how essential this molecule 00:00:33.500 --> 00:00:36.759 is way beyond just humans. It's ancient. Absolutely. 00:00:37.240 --> 00:00:39.320 And that's actually a great place for us to start 00:00:39.320 --> 00:00:42.920 today. Welcome back to The Deep Dive. We are 00:00:42.920 --> 00:00:45.420 really going deep on insulin this time. We are. 00:00:45.539 --> 00:00:47.479 And for this, we've pulled together quite a range 00:00:47.479 --> 00:00:50.119 of sources where we're looking at the core science 00:00:50.119 --> 00:00:52.820 from research papers, medical guidelines, but 00:00:52.820 --> 00:00:55.920 also regulatory info, historical accounts, trying 00:00:55.920 --> 00:00:58.700 to get that full picture. Right. So for you, 00:00:58.780 --> 00:01:01.380 the learner, our mission here is to unpack this 00:01:01.380 --> 00:01:03.880 really critical hormone. We want you to walk 00:01:03.880 --> 00:01:07.620 away with a solid understanding of where it came 00:01:07.620 --> 00:01:10.739 from, how it works, how it's made, which is fascinating 00:01:10.739 --> 00:01:13.780 in itself, the rules around it, the controversies 00:01:13.780 --> 00:01:17.340 even, and just its massive impact. OK, so let's 00:01:17.340 --> 00:01:20.420 jump right in. What is insulin fundamentally? 00:01:21.340 --> 00:01:23.700 Well, at its core, it's what we call a peptide 00:01:23.700 --> 00:01:26.579 hormone. So basically a protein built from amino 00:01:26.579 --> 00:01:29.400 acids acting as a messenger. And it's produced 00:01:29.400 --> 00:01:31.760 by very specific cells, the beta cells, in the 00:01:31.760 --> 00:01:34.620 pancreas. In those islets of Langerhans. That's 00:01:34.620 --> 00:01:36.760 them, little clusters within the pancreas. And 00:01:36.760 --> 00:01:39.260 their main job, the big one, is managing your 00:01:39.260 --> 00:01:41.560 blood glucose, your blood sugar. OK, so how does 00:01:41.560 --> 00:01:44.280 it do that? What's the mechanism? It works in 00:01:44.280 --> 00:01:47.120 primarily two key ways. First, it basically tells 00:01:47.120 --> 00:01:49.969 cells in your body thick muscles, fat tissue. 00:01:50.290 --> 00:01:52.250 Hey, soak up glucose from the blood. Opens the 00:01:52.250 --> 00:01:54.670 door, sorta. Exactly. And second, it signals 00:01:54.670 --> 00:01:58.109 to your liver to put the brakes on making more 00:01:58.109 --> 00:02:00.329 glucose. So it reduces glucose coming into the 00:02:00.329 --> 00:02:02.489 blood and increases glucose leaving it. It's 00:02:02.489 --> 00:02:05.129 a balancing act. Hmm. Sounds pretty sophisticated. 00:02:05.409 --> 00:02:07.329 More than just flipping a switch. Oh, definitely. 00:02:07.709 --> 00:02:10.050 And the molecule itself, it goes through a whole 00:02:10.050 --> 00:02:12.129 production line before it's ready. It starts 00:02:12.129 --> 00:02:14.449 as this inactive precursor, pre -pro insulin. 00:02:14.530 --> 00:02:17.419 Okay. Then inside the cell, in an endoplasmic 00:02:17.419 --> 00:02:19.800 reticulum and Golgi apparatus. Think of them 00:02:19.800 --> 00:02:22.900 as the cell's factory and processing plant. It's 00:02:22.900 --> 00:02:26.240 modified. Bits are snipped off. It folds correctly. 00:02:26.460 --> 00:02:28.340 And you end up with the final active insulin. 00:02:28.500 --> 00:02:31.360 Right. The active form has two chains, A and 00:02:31.360 --> 00:02:34.159 B, linked together by the sulfide bonds. And 00:02:34.159 --> 00:02:36.439 interestingly, when a piece called the C -keptide 00:02:36.439 --> 00:02:39.180 is cut off to make active insulin, it gets released 00:02:39.180 --> 00:02:41.960 too. we can actually measure C -peptide in the 00:02:41.960 --> 00:02:43.900 blood to see how much insulin the body is making 00:02:43.900 --> 00:02:46.439 itself. Ah, that's clever. A useful byproduct. 00:02:46.580 --> 00:02:48.560 And you mentioned earlier this basic structure. 00:02:48.759 --> 00:02:50.479 It's found across lots of different animals. 00:02:50.740 --> 00:02:53.240 Yes. The sequence of amino acids, the blueprint, 00:02:53.819 --> 00:02:56.680 is remarkably similar across species. It's highly 00:02:56.680 --> 00:02:59.930 conserved, evolutionarily speaking. It hammers 00:02:59.930 --> 00:03:03.090 home how vital it is. So even though, say, cow 00:03:03.090 --> 00:03:06.270 or pig insulin isn't identical to human insulin. 00:03:06.629 --> 00:03:08.150 Right. There are small differences, three amino 00:03:08.150 --> 00:03:11.009 acids different in cows, one in pigs. But they 00:03:11.009 --> 00:03:13.430 still work well enough in humans. It shows the 00:03:13.430 --> 00:03:15.969 core function is preserved even with minor tweaks. 00:03:16.330 --> 00:03:19.509 OK. So this hormone is crucial for keeping blood 00:03:19.509 --> 00:03:22.210 sugar stable. What happens when that system goes 00:03:22.210 --> 00:03:24.800 wrong? when you don't have enough or it's not 00:03:24.800 --> 00:03:26.819 working properly. Yeah, that's when we run into 00:03:26.819 --> 00:03:29.780 problems, primarily high blood sugar hyperglycemia, 00:03:29.840 --> 00:03:31.840 which is the hallmark of diabetes. And there 00:03:31.840 --> 00:03:33.819 are the two main types we hear about, type 1 00:03:33.819 --> 00:03:36.180 and type 2. How does insulin play out differently 00:03:36.180 --> 00:03:39.479 there? They are quite distinct. In type 1 diabetes, 00:03:39.599 --> 00:03:42.520 it's an autoimmune issue. The body's own immune 00:03:42.520 --> 00:03:45.960 system mistakenly attacks and wipes out those 00:03:45.960 --> 00:03:48.909 beta cells in the pancreas. So the factory gets 00:03:48.909 --> 00:03:51.409 destroyed, basically. Exactly. The result is 00:03:51.409 --> 00:03:53.490 an almost complete inability to produce insulin. 00:03:53.650 --> 00:03:57.069 It's an absolute deficiency. OK. And type 2 is 00:03:57.069 --> 00:03:59.789 different. Less about destruction, more about 00:03:59.789 --> 00:04:03.509 malfunction. It's generally more complex, yes. 00:04:03.629 --> 00:04:06.430 There can be some beta cell loss in type 2, maybe 00:04:06.430 --> 00:04:08.310 linked to things like amyloid protein buildup 00:04:08.310 --> 00:04:10.270 in the islets, but it's usually not the main 00:04:10.270 --> 00:04:12.509 driver. And it's not typically autoimmune. So 00:04:12.509 --> 00:04:15.250 what is the main issue, then? Often it's a combination. 00:04:15.550 --> 00:04:18.470 The remaining beta cells might not secrete enough 00:04:18.470 --> 00:04:22.189 insulin when needed, and crucially, the body's 00:04:22.189 --> 00:04:25.750 tissues, muscles, fat, liver become resistant 00:04:25.750 --> 00:04:28.029 to the insulin that is there. It's like the locks 00:04:28.029 --> 00:04:30.069 are getting rusty, the key doesn't work as well. 00:04:30.269 --> 00:04:32.189 So the signal isn't getting through properly. 00:04:32.689 --> 00:04:35.370 Precisely. Plus, in type 2, there's often another 00:04:35.370 --> 00:04:38.589 issue. The hormone leukogon, which raises blood 00:04:38.589 --> 00:04:41.680 sugar, isn't properly regulated. It keeps getting 00:04:41.680 --> 00:04:44.519 released even when blood sugar is high. So you've 00:04:44.519 --> 00:04:46.600 got multiple things pushing blood sugar up. Wow, 00:04:46.699 --> 00:04:48.620 okay. So it's not just about less insulin. It's 00:04:48.620 --> 00:04:51.100 also about sensitivity and other hormones getting 00:04:51.100 --> 00:04:53.519 involved. That's a good way to put it. And beyond 00:04:53.519 --> 00:04:55.939 type 1 and 2, you have other conditions too. 00:04:56.379 --> 00:04:59.259 Like insulinomas, rare tumors that make too much 00:04:59.259 --> 00:05:01.980 insulin, causing low blood sugar. And things 00:05:01.980 --> 00:05:04.920 like metabolic syndrome or PCOS are often linked 00:05:04.920 --> 00:05:07.839 with insulin resistance. It really is central 00:05:07.839 --> 00:05:09.519 to so much of our metabolism. Now, obviously, 00:05:09.660 --> 00:05:11.500 we haven't always had insulin available as a 00:05:11.500 --> 00:05:13.560 medicine. It has this incredible history of discovery, 00:05:13.759 --> 00:05:16.500 right? Oh, absolutely. A long and fascinating 00:05:16.500 --> 00:05:18.779 journey. People knew something was wrong with 00:05:18.779 --> 00:05:21.100 the pancreas and diabetes way back in the 19th 00:05:21.100 --> 00:05:23.860 century. But isolating the active substance, 00:05:24.600 --> 00:05:27.139 that took time. The early 20th century was key, 00:05:27.300 --> 00:05:29.779 wasn't it? Banting and Best and McLeod. Yes. 00:05:30.040 --> 00:05:32.240 Their work in the early 1920s, leading to the 00:05:32.240 --> 00:05:34.560 first successful treatments, was monumental. 00:05:34.860 --> 00:05:37.699 But the scientific understanding kept evolving 00:05:37.699 --> 00:05:41.000 rapidly after that. John Jacob Abel crystallized 00:05:41.000 --> 00:05:44.360 insulin in 1926, a huge step for studying its 00:05:44.360 --> 00:05:47.339 chemistry. Getting a pure form. Exactly. And 00:05:47.339 --> 00:05:49.639 researchers like Somogy, Doisy, and Schaffer 00:05:49.639 --> 00:05:51.939 proved it was definitely a protein around 1924. 00:05:52.939 --> 00:05:55.399 Then Jensen and Evans Jr. identified key amino 00:05:55.399 --> 00:05:57.500 acid components like phenylalanine and proline 00:05:57.500 --> 00:06:01.079 in 1935. Little by little, the picture got clearer. 00:06:01.240 --> 00:06:03.779 But figuring out the entire sequence, every single 00:06:03.779 --> 00:06:07.019 amino acid in order, that sounds incredibly difficult 00:06:07.019 --> 00:06:09.600 for the time. It was a Herculean task. Frederick 00:06:09.600 --> 00:06:12.259 Sanger finally cracked it in 1951, determined 00:06:12.259 --> 00:06:14.660 the full amino acid sequence. Groundbreaking 00:06:14.660 --> 00:06:16.339 work earned him a Nobel Prize. Oh, once they 00:06:16.339 --> 00:06:18.279 knew the sequence, could they make it? Well, 00:06:18.379 --> 00:06:21.160 that was the next big challenge. Synthesis, making 00:06:21.160 --> 00:06:24.500 it from scratch in the lab. Two groups, Quetzianices 00:06:24.500 --> 00:06:27.399 and Zans, managed it pretty much simultaneously 00:06:27.399 --> 00:06:30.660 in the mid -1960s, and Chinese scientists also 00:06:30.660 --> 00:06:33.180 synthesized bovine insulin around them. And then 00:06:33.180 --> 00:06:36.579 seeing its actual 3D shape. That came in 1969. 00:06:37.319 --> 00:06:39.939 Dorothy Hodgkin used X -ray crystallography to 00:06:39.939 --> 00:06:42.160 map out its complex three -dimensional structure. 00:06:42.350 --> 00:06:45.149 Another Nobel Prize -winning effort. It took 00:06:45.149 --> 00:06:47.449 decades of brilliant work from many people. An 00:06:47.449 --> 00:06:50.050 amazing scientific story. And for a long time, 00:06:50.170 --> 00:06:52.370 the insulin people used actually came from animals. 00:06:52.629 --> 00:06:54.810 That's right. For many, many years, the source 00:06:54.810 --> 00:06:57.350 was purified insulin from the pancreases of cows 00:06:57.350 --> 00:07:00.029 and pigs. It saved countless lives, absolutely. 00:07:00.430 --> 00:07:02.769 But it wasn't identical to human insulin. And 00:07:02.769 --> 00:07:04.810 sometimes it could cause immune reactions or 00:07:04.810 --> 00:07:06.910 allergies. Which leads us nicely into how insulin 00:07:06.910 --> 00:07:09.410 is used clinically today. What are the main reasons 00:07:09.410 --> 00:07:11.870 someone would need insulin therapy? Well, the 00:07:11.870 --> 00:07:14.350 most obvious is type 1 diabetes, where the body 00:07:14.350 --> 00:07:17.029 makes virtually none. Insulin replacement therapy 00:07:17.029 --> 00:07:19.769 is simply essential for survival there. No question. 00:07:20.230 --> 00:07:22.629 But it's also used quite a lot in type 2 diabetes, 00:07:22.769 --> 00:07:24.589 isn't it? Even though the body might still be 00:07:24.589 --> 00:07:28.610 making some. Yes, absolutely. In type 2, treatment 00:07:28.610 --> 00:07:31.129 usually starts with lifestyle changes. maybe 00:07:31.129 --> 00:07:34.649 metformin or other oral drugs. But if blood sugar 00:07:34.649 --> 00:07:37.029 targets aren't met, or if someone presents with 00:07:37.029 --> 00:07:40.009 really high symptomatic blood sugar, then insulin 00:07:40.009 --> 00:07:43.110 is often the next step. How is it typically started 00:07:43.110 --> 00:07:46.110 in type 2? Often the first step is adding a basal 00:07:46.110 --> 00:07:48.430 insulin that's a longer acting type designed 00:07:48.430 --> 00:07:50.430 to cover the body's background insulin needs 00:07:50.430 --> 00:07:53.550 overnight and between meals. People usually continue 00:07:53.550 --> 00:07:55.649 their other medications alongside it. And then 00:07:55.649 --> 00:07:58.629 sometimes more insulin is needed. Yes. If blood 00:07:58.629 --> 00:08:01.209 sugar still spikes after meals, a bolus insulin 00:08:01.209 --> 00:08:03.810 might be added. This is a rapid -acting type 00:08:03.810 --> 00:08:06.209 taken just before eating to cover the glucose 00:08:06.209 --> 00:08:08.410 coming in from food. We hear about different 00:08:08.410 --> 00:08:10.810 kinds, like analogs. What are those? Insulin 00:08:10.810 --> 00:08:13.089 analogs are basically versions of human insulin 00:08:13.089 --> 00:08:15.110 that have been tweaked, genetically engineered, 00:08:15.569 --> 00:08:17.509 to change how quickly they work or how long they 00:08:17.509 --> 00:08:19.870 last. To make them work better for certain situations. 00:08:20.370 --> 00:08:22.629 Exactly. Rapid -acting analogs, for instance, 00:08:22.889 --> 00:08:25.370 kick in faster and wear off sooner than regular 00:08:25.370 --> 00:08:27.810 human insulin. That can be really helpful for 00:08:27.810 --> 00:08:30.089 matching insulin delivery to meals, potentially 00:08:30.089 --> 00:08:32.070 reducing lows later on. And the long -acting 00:08:32.070 --> 00:08:34.529 ones? Long -acting analogs are designed to provide 00:08:34.529 --> 00:08:37.289 a steadier, peakless background insulin level 00:08:37.289 --> 00:08:41.909 over ideally 24 hours. This predictability is 00:08:41.909 --> 00:08:44.940 a big reason why analogs both rapid and long 00:08:44.940 --> 00:08:47.600 -acting, have become so common, especially in 00:08:47.600 --> 00:08:49.580 type 1 management. Makes sense. And how people 00:08:49.580 --> 00:08:51.559 take insulin has evolved, too, right? It's not 00:08:51.559 --> 00:08:53.940 just vials and syringes anymore. Definitely not. 00:08:54.340 --> 00:08:57.120 Insulin pens, pre -filled devices that make dosing 00:08:57.120 --> 00:08:59.620 easier and more discreet, are hugely popular. 00:08:59.659 --> 00:09:02.120 And then you have insulin pumps. Right, the ones 00:09:02.120 --> 00:09:05.299 that deliver it continuously. Yes, small devices 00:09:05.299 --> 00:09:07.340 worn on the body that deliver insulin through 00:09:07.340 --> 00:09:09.759 a tiny tube under the skin. They offer a lot 00:09:09.759 --> 00:09:12.500 more flexibility and fine tuning. And now, we're 00:09:12.500 --> 00:09:14.519 seeing really exciting advances in automated 00:09:14.519 --> 00:09:17.179 systems. The artificial pancreas type systems. 00:09:17.860 --> 00:09:20.720 Exactly. Hybrid closed -loop systems, sometimes 00:09:20.720 --> 00:09:23.879 called the bionic pancreas, they link a continuous 00:09:23.879 --> 00:09:27.039 glucose monitor with an insulin pump via a smart 00:09:27.039 --> 00:09:30.039 algorithm. The system automatically adjusts insulin 00:09:30.039 --> 00:09:32.659 delivery based on real -time glucose readings. 00:09:32.879 --> 00:09:34.840 That sounds like a game -changer, especially 00:09:34.840 --> 00:09:37.700 for type 1. It really is proving to be. The real 00:09:37.700 --> 00:09:40.019 -world data and patient experiences are incredibly 00:09:40.019 --> 00:09:42.370 positive. It takes away a lot of the constant 00:09:42.370 --> 00:09:45.350 calculation and burden. Amazing progress. OK, 00:09:45.350 --> 00:09:48.629 let's shift gears a bit. How is this stuff actually 00:09:48.629 --> 00:09:51.529 made today? I assume it's a far cry from grinding 00:09:51.529 --> 00:09:54.090 up animal pain creases now. Oh, completely. The 00:09:54.090 --> 00:09:56.649 vast majority of insulin produced today uses 00:09:56.649 --> 00:09:59.389 recombinant DNA technology. It's a biological 00:09:59.389 --> 00:10:01.710 manufacturing process. Which means it's different 00:10:01.710 --> 00:10:04.590 from making a typical chemical drug. Yes, very 00:10:04.590 --> 00:10:05.970 different. Because you're working with living 00:10:05.970 --> 00:10:08.690 cells in complex biological processes, there's 00:10:08.690 --> 00:10:11.980 inherent variability. quality control, risk management. 00:10:12.539 --> 00:10:14.899 They have to be incredibly stringent every step 00:10:14.899 --> 00:10:16.379 of the way. It's not like just mixing chemicals 00:10:16.379 --> 00:10:18.480 A and B. So what are the general steps if you're 00:10:18.480 --> 00:10:21.740 making a biologic like insulin? Well the WHO 00:10:21.740 --> 00:10:24.279 lays out general guidelines. You start with your 00:10:24.279 --> 00:10:26.799 source material, the engineered cells. You process 00:10:26.799 --> 00:10:29.299 them, create carefully controlled cell banks, 00:10:29.659 --> 00:10:32.100 master banks, working banks to ensure consistency. 00:10:32.379 --> 00:10:34.740 Like a library of the producer cells. Sort of, 00:10:34.799 --> 00:10:37.580 yeah. Then you grow these cells in huge batches 00:10:37.580 --> 00:10:40.259 in bioreactors under very specific conditions 00:10:40.259 --> 00:10:43.289 that cell culture or fermentation They produce 00:10:43.289 --> 00:10:45.250 the protein you want, like pro -insulin. And 00:10:45.250 --> 00:10:46.950 then you have to get the insulin out. Right. 00:10:47.129 --> 00:10:49.769 That's the purification stage. Very complex, 00:10:49.990 --> 00:10:51.909 multiple steps to isolate the target protein 00:10:51.909 --> 00:10:53.710 and get rid of everything else, cell debris, 00:10:53.850 --> 00:10:56.610 other proteins, et cetera. Then it might be formulated, 00:10:56.809 --> 00:10:58.409 maybe combined with other things to stabilize 00:10:58.409 --> 00:11:01.009 it or adjust its action profile, and finally 00:11:01.009 --> 00:11:04.049 field into vials or pens. You mentioned recombinant 00:11:04.049 --> 00:11:06.549 DNA. We often hear about E. coli bacteria being 00:11:06.549 --> 00:11:08.850 involved. How do they fit in? E. coli is a real 00:11:08.850 --> 00:11:11.330 workhorse for this. Scientists engineer these 00:11:11.330 --> 00:11:13.889 bacteria by inserting a piece of circular DNA, 00:11:14.470 --> 00:11:17.210 a plasmid, into them. Okay. And this plasmid 00:11:17.210 --> 00:11:19.990 contains the human gene, the instructions for 00:11:19.990 --> 00:11:22.570 making either the A and B chains of insulin separately, 00:11:23.110 --> 00:11:25.169 or the single -chain pro -insulin precursor. 00:11:25.389 --> 00:11:28.070 So the bacteria become tiny insulin factories? 00:11:28.450 --> 00:11:31.350 Essentially, yes. They're grown in large tanks 00:11:31.350 --> 00:11:34.929 with nutrient broth. Often, an antibiotic like 00:11:34.929 --> 00:11:37.779 kanamycin is added. The plasmid also contains 00:11:37.779 --> 00:11:40.200 a gene for resistance to that antibiotic. Ah, 00:11:40.220 --> 00:11:42.639 so only the bacteria that successfully took up 00:11:42.639 --> 00:11:45.220 the insulin -making plasmid survive. Exactly. 00:11:45.240 --> 00:11:48.620 It's a selection mechanism. Then later, techniques 00:11:48.620 --> 00:11:51.000 using special enzymes, restriction enzymes like 00:11:51.000 --> 00:11:54.039 Bamahi, are used. They cut the DNA at specific 00:11:54.039 --> 00:11:56.799 points. Like molecular scissors. Right. And by 00:11:56.799 --> 00:11:59.000 looking at the pattern of DNA fragments produced, 00:11:59.460 --> 00:12:01.000 scientists can confirm that the insulin gene 00:12:01.000 --> 00:12:03.580 is present and correct in the E. coli colonies 00:12:03.580 --> 00:12:05.799 they've selected. It's like checking the genetic 00:12:05.799 --> 00:12:08.500 blueprint is right before mass production. Fascinating. 00:12:08.559 --> 00:12:11.059 A real blend of biology and engineering. Now, 00:12:11.059 --> 00:12:13.259 what about the rules, the regulations around 00:12:13.259 --> 00:12:16.419 insulin? Has that been straightforward? Not always, 00:12:16.460 --> 00:12:18.500 especially in the US. There's some unique history 00:12:18.500 --> 00:12:22.139 there. A very early step was the 1941 Insulin 00:12:22.139 --> 00:12:24.820 Amendment. It actually required the FDA to batch 00:12:24.820 --> 00:12:27.620 test insulin for purity and potency. That was 00:12:27.620 --> 00:12:29.379 quite forward thinking for the time. But it wasn't 00:12:29.379 --> 00:12:31.360 treated like other biologics for a long time. 00:12:31.500 --> 00:12:34.639 That's the key point. Historically, insulin in 00:12:34.639 --> 00:12:37.080 the U .S. was regulated under the Food, Drug, 00:12:37.240 --> 00:12:39.679 and Cosmetic Act, not the Public Health Service 00:12:39.679 --> 00:12:42.840 Act, like most protein therapies, most biologics. 00:12:42.980 --> 00:12:45.919 And that difference mattered? It did. Particularly 00:12:45.919 --> 00:12:48.919 for the approval pathway for biosimilars, those 00:12:48.919 --> 00:12:51.299 highly similar, potentially more affordable versions, 00:12:51.899 --> 00:12:54.350 they had to use a different... arguably more 00:12:54.350 --> 00:12:57.370 complex pathway, the 505b2 pathway, instead of 00:12:57.370 --> 00:13:00.549 the dedicated biosimilar pathway, 351k. But that's 00:13:00.549 --> 00:13:03.350 changed recently, or is changing. Yes, the transition 00:13:03.350 --> 00:13:06.769 happened around 2020. The idea was to bring all 00:13:06.769 --> 00:13:09.289 biologics, including insulin, under that same 00:13:09.289 --> 00:13:12.539 section 351 umbrella in the PHS Act. The hope 00:13:12.539 --> 00:13:14.940 was to streamline biosimilar approvals. Okay, 00:13:15.000 --> 00:13:17.299 so what are biosimilar insulins and what are 00:13:17.299 --> 00:13:19.259 the hurdles? You mentioned affordability. Right. 00:13:19.580 --> 00:13:22.320 A biosimilar is a biologic drug shown to be highly 00:13:22.320 --> 00:13:25.220 similar to an existing approved biologic, the 00:13:25.220 --> 00:13:28.100 reference product. No clinically meaningful differences 00:13:28.100 --> 00:13:31.000 in safety, purity, and potency. Because they 00:13:31.000 --> 00:13:33.440 come from living systems, they aren't exact identical 00:13:33.440 --> 00:13:35.519 copies like small molecule generics. So getting 00:13:35.519 --> 00:13:37.299 them approved requires showing they're really, 00:13:37.299 --> 00:13:40.320 really close. Exactly. And a key concept, particularly 00:13:40.320 --> 00:13:43.340 in the U .S., is interchangeability. This is 00:13:43.340 --> 00:13:46.179 an extra designation. It means a pharmacist can 00:13:46.179 --> 00:13:48.980 substitute the interchangeable biosimilar for 00:13:48.980 --> 00:13:51.440 the original brand name biologic without needing 00:13:51.440 --> 00:13:53.340 to check with the prescriber first. Like how 00:13:53.340 --> 00:13:56.159 generics are substituted now. Pretty much. But 00:13:56.159 --> 00:13:58.220 achieving that interchangeability designation 00:13:58.220 --> 00:14:01.000 requires additional studies and data, and it's 00:14:01.000 --> 00:14:04.139 a high bar set by the FDA. It's seen as crucial 00:14:04.139 --> 00:14:06.519 for driving real market competition and price 00:14:06.519 --> 00:14:09.529 reductions. The approach differs elsewhere though 00:14:09.529 --> 00:14:11.789 the EMA in Europe, for example, doesn't make 00:14:11.789 --> 00:14:13.830 that specific interchangeability call at the 00:14:13.830 --> 00:14:15.669 EU level. Which brings us to the elephant in 00:14:15.669 --> 00:14:18.970 the room. The cost. Insulin prices, especially 00:14:18.970 --> 00:14:21.509 in the U .S., are notoriously high. They are. 00:14:21.690 --> 00:14:24.490 It's a huge issue. Despite insulin being a central 00:14:24.490 --> 00:14:26.909 discovery, the U .S. market is dominated by just 00:14:26.909 --> 00:14:29.309 three main companies. There hasn't been the kind 00:14:29.309 --> 00:14:32.129 of robust biosimilar competition that many hope 00:14:32.129 --> 00:14:34.710 for or that exists for other drugs. And that 00:14:34.710 --> 00:14:37.009 lack of competition is seen as a major driver 00:14:37.009 --> 00:14:39.539 of the high prices. It's certainly a huge factor. 00:14:39.960 --> 00:14:42.299 Prices in the U .S. are dramatically higher than 00:14:42.299 --> 00:14:45.039 in Canada, Europe, other developed nations. It's 00:14:45.039 --> 00:14:47.580 led to significant access and affordability crises 00:14:47.580 --> 00:14:51.620 for many people. Have there been efforts to figure 00:14:51.620 --> 00:14:55.360 out why this is happening beyond just lack of 00:14:55.360 --> 00:14:58.220 competition? Oh, yes. There's been a lot of scrutiny 00:14:58.220 --> 00:15:00.899 on the whole supply chain, particularly the role 00:15:00.899 --> 00:15:04.980 of pharmacy benefit managers. These are the intermediaries 00:15:04.980 --> 00:15:08.220 between manufacturers and health plans. Investigations 00:15:08.220 --> 00:15:10.720 by Congress, the FTC, they're looking into the 00:15:10.720 --> 00:15:12.659 rebate systems and business practices to see 00:15:12.659 --> 00:15:15.059 if they contribute to inflating list prices while 00:15:15.059 --> 00:15:17.399 maybe benefiting the middlemen. Complex stuff. 00:15:17.559 --> 00:15:19.220 Are there solutions being talked about? Well, 00:15:19.460 --> 00:15:20.899 several things are on the table or have been 00:15:20.899 --> 00:15:23.240 tried. Allowing importation from countries like 00:15:23.240 --> 00:15:25.919 Canada is one idea, though it has its own complexities. 00:15:26.519 --> 00:15:28.159 There have been state and federal legislative 00:15:28.159 --> 00:15:31.299 pushes to cap co -pays or somehow control prices. 00:15:32.159 --> 00:15:34.559 And, of course, encouraging more biosimilar entry 00:15:34.559 --> 00:15:36.919 and uptake is still seen as key. How does this 00:15:36.919 --> 00:15:39.360 compare globally? Are other countries handling 00:15:39.360 --> 00:15:41.899 biosimilar insulin regulation differently? It 00:15:41.899 --> 00:15:45.799 really varies. The EU, Japan, Australia, Canada, 00:15:46.139 --> 00:15:48.220 they all have established pathways, maybe with 00:15:48.220 --> 00:15:50.379 slightly different data requirements or approaches 00:15:50.379 --> 00:15:53.200 to interchangeability. Some places, like Brazil, 00:15:53.659 --> 00:15:56.559 even have multiple tiers of biosimilar pathways. 00:15:57.159 --> 00:15:59.159 And you see a growing trend in countries like 00:15:59.159 --> 00:16:04.399 Brazil, Cuba, Iran, China, to develop local manufacturing 00:16:04.399 --> 00:16:07.100 capacity, sometimes through partnerships. It's 00:16:07.100 --> 00:16:09.320 often driven by a desire for better access and 00:16:09.320 --> 00:16:11.620 lower costs. And patents must play a role in 00:16:11.620 --> 00:16:13.759 this competition landscape, too. Absolutely. 00:16:14.320 --> 00:16:16.500 Like with many drugs, companies use various patent 00:16:16.500 --> 00:16:18.740 strategies sometimes called patent thickets on 00:16:18.740 --> 00:16:21.519 the drug itself, the delivery devices, manufacturing 00:16:21.519 --> 00:16:24.360 processes. This can significantly delay the entry 00:16:24.360 --> 00:16:27.259 of biosimilar competitors long after the main 00:16:27.259 --> 00:16:29.840 patent on the molecule has expired. So this whole 00:16:29.840 --> 00:16:31.740 regulatory picture, the competition issues, it 00:16:31.740 --> 00:16:33.820 all has a massive economic impact, doesn't it? 00:16:33.960 --> 00:16:36.720 Huge. Insulin represents a really significant 00:16:36.720 --> 00:16:38.779 chunk of healthcare spending, especially with 00:16:38.779 --> 00:16:41.080 the high U .S. prices. The potential savings 00:16:41.080 --> 00:16:44.139 from wider biosimilar use are substantial, theoretically. 00:16:44.419 --> 00:16:46.080 And the price difference drives things like people 00:16:46.080 --> 00:16:48.409 traveling to buy insulin. Yes, unfortunately. 00:16:48.929 --> 00:16:51.049 The stark price differences between the U .S. 00:16:51.110 --> 00:16:54.389 and, say, Canada or Mexico lead some individuals 00:16:54.389 --> 00:16:56.690 to travel across borders just to afford their 00:16:56.690 --> 00:16:59.690 medication. It highlights the desperation. There's 00:16:59.690 --> 00:17:02.029 also ongoing debate about the cost effectiveness 00:17:02.029 --> 00:17:04.430 of the newer, more expensive analog insulins 00:17:04.430 --> 00:17:07.450 versus the older, cheaper human insulins, especially 00:17:07.450 --> 00:17:09.410 for some people with type 2 diabetes where the 00:17:09.410 --> 00:17:11.450 clinical benefit difference might be less pronounced 00:17:11.450 --> 00:17:13.730 than in type 1. Beyond the dollars and cents, 00:17:13.930 --> 00:17:17.299 though, insulins impact on, well, on culture 00:17:17.299 --> 00:17:20.019 and just daily life for people with diabetes. 00:17:20.619 --> 00:17:22.960 It's profound. Completely transformative. You 00:17:22.960 --> 00:17:25.099 have to remember, before insulin, type 1 diabetes 00:17:25.099 --> 00:17:27.900 was fatal, usually very quickly. Insulin turned 00:17:27.900 --> 00:17:30.480 it into a manageable, albeit challenging, chronic 00:17:30.480 --> 00:17:33.039 condition. It gave people their lives back. And 00:17:33.039 --> 00:17:35.079 even today, the type of insulin regimen someone 00:17:35.079 --> 00:17:37.339 uses can really affect their day -to -day experience, 00:17:37.519 --> 00:17:40.009 can't it? Definitely. We look at patient -reported 00:17:40.009 --> 00:17:42.730 outcomes, or PROs. How satisfied are people with 00:17:42.730 --> 00:17:44.970 their treatment? How does it impact their quality 00:17:44.970 --> 00:17:48.329 of life? Studies comparing, say, basal bolus 00:17:48.329 --> 00:17:50.589 injections multiple times a day versus using 00:17:50.589 --> 00:17:53.170 simpler premixed insulin show varied results. 00:17:53.670 --> 00:17:56.109 Things like convenience, fear of needles, complexity. 00:17:56.319 --> 00:17:58.900 They all play a role in how people feel about 00:17:58.900 --> 00:18:01.740 their therapy. And sometimes responses can even 00:18:01.740 --> 00:18:03.819 differ across ethnic groups. And just sticking 00:18:03.819 --> 00:18:06.359 with insulin therapy can be hard. Adherence is 00:18:06.359 --> 00:18:09.079 a big issue. It really is. Particularly in type 00:18:09.079 --> 00:18:11.759 2 diabetes, a surprising number of people don't 00:18:11.759 --> 00:18:13.839 take their insulin as prescribed consistently. 00:18:14.460 --> 00:18:16.299 Or they stop taking it altogether. That's called 00:18:16.299 --> 00:18:18.980 persistence. Why is that? Is it just the injections? 00:18:19.240 --> 00:18:21.400 That's part of it, for sure. The frequency, the 00:18:21.400 --> 00:18:23.839 timing, the planning involved. It can feel like 00:18:23.839 --> 00:18:25.980 a huge burden, but it's also about perceptions. 00:18:26.740 --> 00:18:28.660 Some people might see starting insulin as a personal 00:18:28.660 --> 00:18:31.079 failure or assign their conditions getting much 00:18:31.079 --> 00:18:33.930 worse. Healthcare provider communication is critical 00:18:33.930 --> 00:18:35.849 here, understanding those patient perceptions, 00:18:36.569 --> 00:18:38.809 explaining the benefits clearly, addressing fears, 00:18:39.450 --> 00:18:41.589 building that trusting relationship is key. It 00:18:41.589 --> 00:18:44.109 sounds like managing insulin involves so much 00:18:44.109 --> 00:18:46.809 more than just the medicine itself. It's psychological, 00:18:47.049 --> 00:18:49.589 behavioral. Absolutely. It requires significant 00:18:49.589 --> 00:18:52.829 patient education, ongoing support, and a collaborative 00:18:52.829 --> 00:18:54.630 approach between the patient and their healthcare 00:18:54.630 --> 00:18:58.460 team to overcome those barriers and achieve good 00:18:58.460 --> 00:19:01.339 long -term outcomes. It's truly remarkable. We've 00:19:01.339 --> 00:19:04.140 gone from, you know, a mysterious substance in 00:19:04.140 --> 00:19:07.200 the pancreas to these incredibly sophisticated 00:19:07.200 --> 00:19:09.779 delivery systems and manufacturing processes, 00:19:10.240 --> 00:19:12.420 yet we're still grappling with issues of access 00:19:12.420 --> 00:19:15.299 and cost a century later. It's that contrast, 00:19:15.380 --> 00:19:17.640 isn't it? The incredible scientific progress 00:19:17.640 --> 00:19:19.980 alongside the persistent societal challenges. 00:19:20.480 --> 00:19:22.700 Insulin embodies that, perhaps more than any 00:19:22.700 --> 00:19:25.119 other medicine. So thinking about this whole 00:19:25.119 --> 00:19:27.920 journey, this deep dive, It's history, the science, 00:19:28.059 --> 00:19:30.500 the economics, the human impact. What's the final 00:19:30.500 --> 00:19:32.640 thought for our listeners to chew on? Hmm, maybe 00:19:32.640 --> 00:19:35.319 this. Considering insulin's century -long history 00:19:35.319 --> 00:19:37.779 and how fundamental it is, what does the future 00:19:37.779 --> 00:19:41.000 hold? Not just for making better insulin or better 00:19:41.000 --> 00:19:43.920 delivery systems, but for ensuring everyone who 00:19:43.920 --> 00:19:46.480 needs this life -saving medicine can actually 00:19:46.480 --> 00:19:48.500 get it and afford it wherever they are in the 00:19:48.500 --> 00:19:50.299 world. That seems like the next big frontier.