TMG-123, a novel glucokinase activator, exerts durable effects on hyperglycemia without increasing triglyceride in diabetic animal models

Abstract

Glucokinase (GK) plays a critical role for maintaining glucose homeostasis with regulating glucose uptake in liver and insulin secretion in pancreas. GK activators have been reported to decrease blood glucose levels in patients with type 2 diabetes mellitus. However, clinical development of GK activators has failed due to the loss of glucose-lowering effects and increased plasma triglyceride levels after chronic treatment. Here, we generated a novel GK activator, TMG-123, examined its in vitro and in vivo pharmacological characteristics, and evaluated its risks of aforementioned clinical issues. TMG-123 selectively activated GK enzyme activity without increasing Vmax. TMG-123 improved glucose tolerance without increasing plasma insulin levels in both insulin-deficient (Goto-Kakizaki rats) and insulin-resistant (db/db mice) models. The beneficial effect on glucose tolerance was greater than results observed with clinically available antidiabetic drugs such as metformin and glibenclamide in Zucker Diabetic Fatty rats. TMG-123 also improved glucose tolerance in combination with metformin. After 4 weeks of administration, TMG-123 reduced the Hemoglobin A1c levels without affecting liver and plasma triglyceride levels in Goto-Kakizaki rats and Diet-Induced Obesity mice. Moreover, TMG-123 sustained its effect on Hemoglobin A1c levels even after 24 weeks of administration without affecting triglycerides. Taken together, these data indicate that TMG-123 exerts glucose-lowering effects in both insulin-deficient and -resistant diabetes, and sustains reduced Hemoglobin A1c levels without affecting hepatic and plasma triglycerides even after chronic treatment. Therefore, TMG-123 is expected to be an antidiabetic drug that overcomes the concerns previously reported with other GK activators.

Ex Vivo Method to Simultaneously Evaluate Glucose Utilization, Uptake, and Production in Rat Liver

“…10 It has also been known that pharmacological activation of hepatic glucokinase increases hepatic glucose uptake by enhancing the first metabolic reaction of glycolysis. 7 In our liver perfusion study, we showed that hepatic glucose production in Goto-Kakizaki rats was higher compared to Wistar rats and the administration of GKA increased hepatic glucose uptake. These results were consistent with previous reports, and therefore, we considered that our method can evaluate physiological responses of hepatic glucose metabolism correctly.…”

“…TMG-123, a GKA, was synthesized in Teijin Pharma Limited (Tokyo, Japan). 7 All other reagents were analytical grade. Ultrapure water purified by a Milli-Q Integral 10 system (Merck Millipore, MA) was used throughout the study.…”

<p>A Recent Achievement In the Discovery and Development of Novel Targets for the Treatment of Type-2 Diabetes Mellitus</p>

“…Some agents like AZD6370, piragliatin, DS-7309, and ARRY-403 also terminated their drug development due to toxicity and loose of effectiveness with long-term administration. [47][48][49][50][51] Some examples of the GK activator presented in Table 3 with their stage of development and company.…”

Implications for Drug Characterization in Glucose Tolerance Tests Without Insulin: Simulation Study of Power and Predictions Using Model‐Based Analysis

“…These samples are analyzed with regard to glucose and insulin to generate dynamic profiles in the absence and presence of the study compound. Preclinically, the glucose protocols differ slightly from other glucose administrations (e.g., intraperitoneal), different duration of, or no, fasting prior to glucose challenge, but, most importantly, sometimes only measuring glucose …”

“…Preclinically, the glucose protocols differ slightly from other glucose administrations (e.g., intraperitoneal), different duration of, or no, fasting prior to glucose challenge, but, most importantly, sometimes only measuring glucose. [6][7][8] Pharmacometric analysis based on time-course data is increasingly used in drug development, due to its integrative nature and the ease with which it can handle dynamic relationships. [9][10][11] There are several examples in which pharmacometric analysis has been shown to be highly powerful in phase II trials.…”