Antidiabetic potential of a novel dual-target activator of glucokinase and peroxisome proliferator activated receptor-γ.

Abstract

BACKGROUND AND PURPOSE:

Glucokinase (GK) balances blood glucose levels via regulation of glucose metabolism and insulin secretion. Peroxisome proliferator activated receptor-γ (PPARγ) regulates gene expression in glucose and lipid metabolism. In this study, we investigated the therapeutic effect of a novel compound, SHP289-03, which activates both GK and PPARγ.

METHODS:

Glucose metabolism was tested in primary hepatocytes of normal ICR mice, and insulin secretion was measured in NIT-1 insulinoma cells as well as in primary islets of normal ICR mice. The in vivo pharmacodynamics of SHP289-03 was assessed using the spontaneous type 2 diabetic mouse model, KKA(y).

KEY RESULTS:

In hepatocytes, SHP289-03 promoted glucose consumption. In NIT-1 cells, it increased the concentration of intracellular ATP and calcium, and subsequently enhanced glucose-stimulated insulin secretion in both NIT-1 cells and primary islets. Moreover, SHP289-03 decreased the blood glucose level, improved glucose tolerance and reduced blood lipid levels in KKA(y) mice. It restored islet morphology and increased the beta cell/alpha cell mass ratio, in addition to up-regulating GK gene expression in the liver of KKA(y) mice.

DISCUSSION AND CONCLUSIONS:

SHP289-03 has significant therapeutic potential for the treatment of diabetes mellitus.

• Authors: Lei Lei, Quan Liu, Shuainan Liu, Yi Huan, Sujuan Sun, Zhiyu Chen, Linyi Li, Zhiqiang Feng, Yan Li, Zhufang Shen
• Journal: Metabolism: clinical and experimental (Metabolism) Vol. 64 Issue 10 Pg. 1250-61 (Oct 2015) ISSN: 1532-8600 [Electronic] United States
• PMID: 26189598 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• 6-(5-(3-fluorobenzyloxy)-2-propoxybenzamido)nicotinic acid
• Benzamides
• Enzyme Activators
• Hypoglycemic Agents
• Nicotinic Acids
• PPAR gamma
• Thiazolidinediones
• Rosiglitazone
• Glucokinase
• Glucose

Topics

• 3T3-L1 Cells
• Adipocytes (drug effects, metabolism)
• Animals
• Benzamides (pharmacology)
• Cells, Cultured
• Enzyme Activators (pharmacology)
• Glucokinase (metabolism)
• Glucose (metabolism)
• Hepatocytes (drug effects, metabolism)
• Hypoglycemic Agents (pharmacology)
• Male
• Mice
• Mice, Inbred ICR
• Mice, Mutant Strains
• Nicotinic Acids (pharmacology)
• PPAR gamma (agonists, metabolism)
• Rats
• Rats, Sprague-Dawley
• Rosiglitazone
• Thiazolidinediones (pharmacology)