Diabetes Mellitus Part 2 - Insulin Therapy
Well, this week I want to talk about insulin. If you remember from the last blog, insulin is a hormone that is produced with the pancreatic beta cells, and although it has several actions, the most important for today’s discussion is blood glucose regulation.
Those of you who know me realize that I love interesting facts. Did you know that canine insulin and porcine (pig) insulin have DNA that is 100% homologous? Cool, huh? Feline insulin and bovine (cow) insulin only have one amino acid difference in their DNA. These differences used to play a huge role in insulin selection for us in veterinary medicine, but bovine and porcine insulins have completely disappeared on the human market.
Along the same vein, canine insulin only has one amino acid difference with human insulin, and feline insulin has four amino acid differences. This is actually important to us since we so often use synthetic human insulins, but we will talk about this more later.
Insulin has a tendency to form dimers (two insulin molecules joined together) or hexamers (six insulin molecules joined together) in solution, but insulin is only biologically active when it is a single strand. Now, if you put zinc in the solution, the insulin molecules will bind around that zinc and form crystals.
You may be wondering why in the world I just had a biochemistry lesson for you! Actually, that concept of insulin binding to zinc is really important to understand as we discuss the formulations of insulin. So, here goes!
Regular insulin is a short acting insulin. Basically, there is no zinc in that insulin, and the insulin contains no crystals – it looks clear. Regular insulin is absorbed quickly, and it works quickly. Its duration of action is only 4-6 hours, though. This makes regular insulin a great option for sick, hospitalized diabetic patients, but since it needs to be given 4-6 times daily, it doesn’t make a great maintenance insulin.
There are several insulins, including NPH (Humulin-N®, Novolin-N®), lente (Vetsulin®), and PZI (ProZinc®), that are considered intermediate acting insulins. The insulin crystallizes around either zinc or protamine, and the crystals settle to the bottom of the suspension. The insulin bottle then needs to be gently rolled to re-suspend these crystals in the solution before giving an injection of insulin. These crystals then must break down in the subcutaneous tissue in our diabetic pets, and this can lead to erratic absorption of insulin. We have been taught in veterinary school that these insulins typically have their peak effect at 6 hours post-injection, but in truth, that peak effect is variable from animal to animal and even day to day in the same animal. Now, that being said, these are still very good insulins, and we will continue to use them, especially since they are generally very cost effective.
In human medicine, synthetic insulins have taken over the market, and the primary reason is variability in absorption. These synthetic insulins vary in the last 7 amino acids in their change, and this affects crystallization and precipitation. Although there are short acting synthetic insulins, we will talk for a few minutes about long acting insulins.
Lantus® (glargine) is a clear insulin that requires no rolling. This insulin has 2 arginines (amino acids) added to the end of the insulin molecule. These two arginines make the insulin dissolve completely in a pH of 4 – this is a suspension with NO CRYSTALS to mix back into solution. When the insulin is injected subcutaneously in a patient, the pH underneath the skin in approximately 7. In a pH of 7, the molecules precipitate, which then allows this insulin to have a long duration of action. Most insulins cause glucose concentrations to decrease until they reach their nadir (lowest point), and then as the insulin wears off, the glucoses slowly rise. Glargine is considered a peakless insulin, at least in people, and the glucoses don’t fluctuate much. Now, this insulin really hasn’t been used much in dogs, but it works well in cats. Cats have more variability, and they really aren’t considered peakless when compared to people. However, this is a very effective insulin for our feline patients.
Toujeo® is a new glargine formulation. It is a U-300 insulin, which means it has 300 units of insulin per mL (other human insulins are U-100, and our veterinary insulins are even lower concentrations at U-40). This insulin is longer acting than glargine with less variability in glucoses. This form of glargine seems to work well in both dogs and cats. There isn’t much data out there yet, but we will continue to watch for it, especially since this may prove to be effective as a once daily injection for both species.
Levemir® (detemir) is another long-acting insulin. Although it doesn’t last anywhere near as long as glargine in people, it is considered a once daily insulin because of its unique properties. Detemir doesn’t have an amino acid on the end of the insulin molecule, it has a fatty acid. This changes the character of the insulin so that it has a hydrophilic (water loving) end and a hydrophobic (water hating) end. The hydrophobic ends stick together in the body in a liquid form, and crystals never form. This hydrophobic structure dissolves more consistently, and as it dissolves, the hydrophobic end binds to albumin (a protein in the body). This allows for more constant blood levels of insulin, which actually decreases the risk of hypoglycemia. Now, we don’t have a lot of information about this insulin yet, either, but it seems to work well in dogs. They use a MUCH lower dose of detemir than other insulins, and we are using it twice daily. This insulin comes in a pen, and this actually makes it more precise, more accurate, and easier to use. Even though this insulin is wicked expensive, it is stable in the refrigerator for months.
I need to come back to homology between the insulins for a quick second. Part of the reason that we always worried about using a homologous insulin was antibody formation to a foreign protein. Interestingly, approximately 20% of cats will develop anti-insulin antibodies, but they do not seem to affect glycemic control, and approximately 50% of humans will develop anti-insulin antibodies to synthetic human insulin. The antibodies don’t adversely affect their glycemic control, either.
Well, I need to wrap this up. To summarize, there are three basic durations of insulin activity, short, intermediate, and long, and the potency varies reciprocally with duration of activity. We have often chosen insulins based upon the duration of activity. However, as more and more new synthetic insulins become available, they offer different degrees of variability in glucose levels in the body, allowing insulin therapy to be safer with lower risk of hypoglycemia. As such, I think that determir and glargine (both Lantus® and Toujeo®) will become the rock stars in the veterinary insulin market.
Insulin Association State and Absorption Rate http://www.japi.org/january_2014_special_issue/03_translating_structure_to.html
Variability in pharmacodynamics of NPH vs. glargine vs. detemir by Heise et al., Diabetes 2004
Molecular structures of all insulins found on rxlist.com