scholarly journals A novel glucokinase activator TMG-123 causes long-lasting hypoglycemia and impairs spermatogenesis irreversibly in rats

2021 ◽  
Vol 46 (3) ◽  
pp. 115-123
Author(s):  
Taiki Kobayashi ◽  
Takasumi Shimomoto ◽  
Azusa Tamura ◽  
Junichi Namekawa ◽  
Takeshi Iijima ◽  
...  
Keyword(s):  
Glucokinase Activator

scholarly journals The Capacity to Secrete Insulin Is Dose-Dependent to Extremely High Glucose Concentrations: A Key Role for Adenylyl Cyclase

Metabolites ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 401
Author(s):  
Katherine M. Gerber ◽  
Nicholas B. Whitticar ◽  
Daniel R. Rochester ◽  
Kathryn L. Corbin ◽  
William J. Koch ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Adenylyl Cyclase ◽  
Human Islets ◽  
Adenylyl Cyclase Activity ◽  
World Record ◽  
Glucokinase Activator ◽  
Amplifying Pathway ◽  
Dose Dependent ◽  
Adenylyl Cyclase Inhibitor ◽  
Cyclase Activator

Insulin secretion is widely thought to be maximally stimulated in glucose concentrations of 16.7-to-30 mM (300-to-540 mg/dL). However, insulin secretion is seldom tested in hyperglycemia exceeding these levels despite the Guinness World Record being 147.6 mM (2656 mg/dL). We investigated how islets respond to 1-h exposure to glucose approaching this record. Insulin secretion from human islets at 12 mM glucose intervals dose-dependently increased until at least 72 mM glucose. Murine islets in 84 mM glucose secreted nearly double the insulin as in 24 mM (p < 0.001). Intracellular calcium was maximally stimulated in 24 mM glucose despite a further doubling of insulin secretion in higher glucose, implying that insulin secretion above 24 mM occurs through amplifying pathway(s). Increased osmolarity of 425-mOsm had no effect on insulin secretion (1-h exposure) or viability (48-h exposure) in murine islets. Murine islets in 24 mM glucose treated with a glucokinase activator secreted as much insulin as islets in 84 mM glucose, indicating that glycolytic capacity exists above 24 mM. Using an incretin mimetic and an adenylyl cyclase activator in 24 mM glucose enhanced insulin secretion above that observed in 84 mM glucose while adenylyl cyclase inhibitor reduced stimulatory effects. These results highlight the underestimated ability of islets to secrete insulin proportionally to extreme hyperglycemia through adenylyl cyclase activity.

Dose-ranging study with the glucokinase activator AZD1656 in patients with type 2 diabetes mellitus on metformin

2013 ◽  
Vol 15 (8) ◽  
pp. 750-759 ◽  
Author(s):  
J. P. H. Wilding ◽  
M. Leonsson-Zachrisson ◽  
C. Wessman ◽  
E. Johnsson
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Glucokinase Activator ◽  
Dose Ranging

Chapter 3. The Discovery of Piragliatin, a Glucokinase Activator

2010 ◽  
pp. 51-70
Author(s):  
Ramakanth Sarabu ◽  
Jefferson W. Tilley ◽  
Joseph Grimsby
Keyword(s):  
Glucokinase Activator

Decoration of an α-Resorcylate Nucleus as Part of the Manufacture of a Glucokinase Activator

2018 ◽  
Vol 22 (8) ◽  
pp. 996-1006 ◽  
Author(s):  
Phillip Hopes ◽  
Thomas Langer ◽  
Kirsty Millard ◽  
Alan Steven
Keyword(s):  
Glucokinase Activator

scholarly journals Targeting hepatic glucokinase to treat diabetes with TTP399, a hepatoselective glucokinase activator

2019 ◽  
Vol 11 (475) ◽  
pp. eaau3441 ◽  
Author(s):  
Adrian Vella ◽  
Jennifer L. R. Freeman ◽  
Imogene Dunn ◽  
Kit Keller ◽  
John B. Buse ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Plasma Lipids ◽  
Regulatory Protein ◽  
Density Lipoprotein ◽  
Loss Of Function ◽  
Therapeutic Success ◽  
Double Blind ◽  
Glucokinase Activator ◽  
Clinically Significant

The therapeutic success of interventions targeting glucokinase (GK) activation for the treatment of type 2 diabetes has been limited by hypoglycemia, steatohepatitis, and loss of efficacy over time. The clinical characteristics of patients with GK-activating mutations or GK regulatory protein (GKRP) loss-of-function mutations suggest that a hepatoselective GK activator (GKA) that does not activate GK in β cells or affect the GK-GKRP interaction may reduce hyperglycemia in patients with type 2 diabetes while limiting hypoglycemia and liver-associated adverse effects. Here, we review the rationale for TTP399, an oral hepatoselective GKA, and its progression from preclinical to clinical development, with an emphasis on the results of a randomized, double-blind, placebo- and active-controlled phase 2 study of TTP399 in patients with type 2 diabetes. In this 6-month study, TTP399 (800 mg/day) was associated with a clinically significant and sustained reduction in glycated hemoglobin, with a placebo-subtracted least squares mean HbA1c change from baseline of −0.9% (P < 0.01). Compared to placebo, TTP399 (800 mg/day) also increased high-density lipoprotein cholesterol (3.2 mg/dl; P < 0.05), decreased fasting plasma glucagon (−20 pg/ml; P < 0.05), and decreased weight in patients weighing ≥100 kg (−3.4 kg; P < 0.05). TTP399 did not cause hypoglycemia, had no detrimental effect on plasma lipids or liver enzymes, and did not increase blood pressure, highlighting the importance of tissue selectivity and preservation of physiological regulation when targeting key metabolic regulators such as GK.

Discovery and preclinical development of AR453588 as an anti-diabetic glucokinase activator

2020 ◽  
Vol 28 (1) ◽  
pp. 115232
Author(s):  
Ronald J. Hinklin ◽  
Brian R. Baer ◽  
Steven A. Boyd ◽  
Mark D. Chicarelli ◽  
Kevin R. Condroski ◽  
...  
Keyword(s):  
Preclinical Development ◽  
Glucokinase Activator
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