Author: Sheri R. Colberg, PhD, FACSM
Have you heard of TTP399? Despite its completely forgettable name used in clinical trials, this potential new oral medication may have the power to lower and stabilize blood glucose in people with type 1 diabetes (T1D). If approved, TTP399 (which would be given a spiffy new brand name) will be the first oral pill to treat T1D. You’ll still need insulin, but TTP399 should lower blood glucose without raising the risk of diabetic ketoacidosis (DKA), and it won’t increase the risk for low blood glucose either.
So, how does this new drug work and why should you get excited about it? TTP399 works on your liver to activate an enzyme called glucokinase. You may be wondering, what is glucokinase and why does it need to be activated? And why isn’t it already activated in people with T1D?
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 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 usual balance of insulin and glucagon—with insulin rising after meals and glucagon rising during fasting and exercise—that signals the liver what to do to keep your blood glucose normal 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. The result: Both a lesser storage of glycogen in the liver and an excess release of glucose after meals and overnight due to glucagon being unchecked by insulin.
This is why glucokinase activation is so important. Activated glucokinase stimulates glucose uptake from the blood and synthesis and storage of glucose in the liver as glycogen (1,2). Having it normally activated would make you need less insulin on a daily basis because your liver would take up and store blood glucose after meals like it is supposed to.
In the pancreas, activated glucokinase acts as a glucose sensor in the beta cells, allowing rising glucose levels to stimulate insulin secretion when glucokinase is activated in people with T2D or anyone with T1D with any insulin-making capacity left (3). In the alpha cells, glucagon secretion is normally triggered by hypoglycemia and suppressed by high glucose levels, but impaired suppression of glucagon is a hallmark of diabetes—in T1D due to insulin deficiency and in T2D due to insulin resistance and/or deficiency (4). Glucose sensing in the alpha cells can limit the release of glucagon but—you guessed it—that also requires activated glucokinase (4). When inactive, too much glucagon gets released and raises your blood glucose—even after meals when your levels are already higher.
How does this all impact exercise? If your liver has been stimulated by activated glucokinase to store more glycogen pre-exercise, you should have more to release to keep your blood glucose from dropping when you are active (since glucagon rises 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.
You really 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. In the SimpliciT1 study (5), 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 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.
TTP399 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. Let’s hope that the final trials being done on this medication prove it to be as effective as the earlier ones.
- 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.
- 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.
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).
See more about TTP399: Daily Pill Optimizes Insulin Use and Reduces A1c For Type 1 Diabetes