Dr. Sheri Colberg-Ochs is a leader in the field of Diabetes Exercise Physiology, Author of 12 books and Owner of Diabetes Motion Academy. Dr. Colberg does extensive work with American Diabetes Association and is a educator in the field for Diabetes.
Her authored books are at the end of this article and are full of detailed information, she has taught me a incredible amount of information through her published work and programs. MedeXN fitness institute offers a very detailed course for trainers looking to learn more about the Medical Exercise Field – Sheri Colberg’s -Diabetes Exercise Specialty is a 3 part program!
Here is her latest article as it relates to TTP399-new oral medication for Type 1 Diabetes.
TTP399 is a potential new glucose-lowering medication for people with type 1 diabetes that was recently given breakthrough therapy designation by the U.S. FDA. This designation provides the developer with added support and the potential to expedite development and review timelines for a promising new medicine. If approved, TTP399 (which would be given a brand name) would be the first oral pill for people with type 1 diabetes (T1D) to treat their diabetes along with insulin.
In the SimpliciT1 study (1), use of TTP399 resulted in both a decrease in A1C and in the amount of insulin that participants needed over 12 weeks, including 11 percent less insulin for meals, as well as two more hours a day with their glucose levels in an optimal range. Apparently, even with less insulin on board and a lower risk for hypoglycemia, people were not more likely to develop diabetic ketoacidosis (DKA), thus avoiding the major pitfall of medications like SGLT-2 inhibitors that have been used off-label (that is, without FDA approval) by some with T1D that can lead to DKA even with normal blood glucose levels.
How does this new medication work? It activates glucokinase in the liver. But what is “glucokinase” and why does it need to be activated? And why isn’t it already activated in people with T1D? So many questions, so little time…
I actually know a thing or two about glucokinase given that my PhD work was in glucose and fatty acid turnover during exercise. As you may know, the liver plays a central role in maintaining a normal blood glucose level, which it accomplishes by storing or releasing glucose depending on your blood glucose levels and activities—assuming everything works well with insulin and glucagon production and release by the pancreas.
Normally, the beta cells of the pancreas make insulin while the alpha cells make glucagon. What happens in T1D is that insulin release from the pancreas is insufficient or absent altogether, and the normal balance of insulin rising after meals and glucagon rising during fasting and exercise that normally signals the liver what to do is lost. Even when you replace insulin through injections, pumping, or inhalation, it never reaches as high of levels as normal in the liver circulation, causing a “sleeping liver” with key metabolic enzymes never being activated. Both a lesser storage of glycogen in the liver and excess release of glucose after meals and overnight due to the effects of glucagon can result.
This is why glucokinase activation is important. Glucokinase is a key enzyme that, when activated, stimulates glucose uptake from the blood and synthesis and storage of glucose in the liver as glycogen (2,3). It also serves as a glucose sensor in pancreatic beta cells and stimulates insulin secretion when activated in people with T2D or anyone with T1D with any insulin-making capacity left (4). Glucagon secretion by pancreatic alpha cells is normally triggered by hypoglycemia and suppressed by high glucose levels, but impaired suppression of glucagon secretion is a hallmark of diabetes—in T1D due to insulin deficiency and in T2D due to insulin resistance and/or deficiency (5). Glucose sensing in the alpha cells of the pancreas to limit the release of glucagon—you guessed it—also requires activated glucokinase (5), and when it remains inactive, too much glucagon gets released and raises your blood glucose—even after meals when your levels are already higher.
Having your glucokinase get activated like normal would make you need less insulin on a daily basis because your liver would take up and store of your blood glucose after meals like it is supposed to. When you exercise, if your liver has been stimulated by activated glucokinase to store more glycogen, you should have more to release to keep your blood glucose from dropping during activities (since glucagon levels rise during physical activity), and you would be less likely to experience lows during and even following exercise. Sufficiently activated glucokinase in your pancreatic alpha cells should also reduce those pesky glucose elevations frequently experienced in the early morning hours by many people.
So, yes, you do want your glucokinase activation to be back up to normal in your liver and your pancreas, and TTP399 may just prove to be the way to do that in people with T1D. Let’s hope that the final trials being done on this medication prove it to be as effective as the earlier ones.
References:
- Klein KR, Freeman JLR, Dunn I, Dvergsten C, Kirkman MS, Buse JB, Valcarce C; SimpliciT1 research group. The SimpliciT1 Study: A Randomized, Double-Blind, Placebo-Controlled Phase 1b/2 Adaptive Study of TTP399, a Hepatoselective Glucokinase Activator, for Adjunctive Treatment of Type 1 Diabetes. Diabetes Care. 2021 Apr;44(4):960-968.
- Adeva-Andany MM, González-Lucán M, Donapetry-García C, Fernández-Fernández C, Ameneiros-Rodríguez E. Glycogen metabolism in humans. BBA Clin. 2016 Feb 27;5:85-100.
- Matschinsky FM, Wilson DF. The Central Role of Glucokinase in Glucose Homeostasis: A Perspective 50 Years After Demonstrating the Presence of the Enzyme in Islets of Langerhans. Front Physiol. 2019 Mar 6;10:148.
- Toulis KA, Nirantharakumar K, Pourzitaki C, Barnett AH, Tahrani AA. Glucokinase Activators for Type 2 Diabetes: Challenges and Future Developments. Drugs. 2020 Apr;80(5):467-475.
- Basco, D., Zhang, Q., Salehi, A., Tarasov, A., Dolci, W., Herrera, P., et al. (2018). α-cell glucokinase suppresses glucose-regulated glucagon secretion. Nat. Commun. 9, 1–9.
Sheri R. Colberg, PhD, is the author of The Athlete’s Guide to Diabetes: Expert Advice for 165 Sports and Activities (the newest edition of Diabetic Athlete’s Handbook). She is also the author of Diabetes & Keeping Fit for Dummies,co-published by Wiley and the ADA. A professor emerita of exercise science from Old Dominion University and an internationally recognized diabetes motion expert, she is the author of 12 books, 34 book chapters, and over 420 articles. She was honored with the 2016 American Diabetes Association Outstanding Educator in Diabetes Award. Contact her via her websites (SheriColberg.com and DiabetesMotion.com).