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Journal Article
Research Support, Non-U.S. Gov't
Antidiabetic potential of a novel dual-target activator of glucokinase and peroxisome proliferator activated receptor-γ.
Metabolism: Clinical and Experimental 2015 October
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.
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.
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