title: Antidiabetic potential of a novel dual-target activator of glucokinase and peroxisome proliferator activated receptor-γ.
abstract: OBJECTIVE
  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).
  
  
  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.
  
  
  CONCLUSIONS
  SHP289-03 has significant therapeutic potential for the treatment of diabetes mellitus.
authors.affiliation: The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P. R. China.
authors.forename: Lei
authors.initials: L
authors.lastname: Lei
authors.affiliation: The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P. R. China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Liu
authors.affiliation: The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P. R. China.
authors.forename: Shuainan
authors.initials: S
authors.lastname: Liu
authors.affiliation: The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P. R. China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Huan
authors.affiliation: The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P. R. China.
authors.forename: Sujuan
authors.initials: S
authors.lastname: Sun
authors.affiliation: The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P. R. China.
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Chen
authors.affiliation: The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P. R. China.
authors.forename: Linyi
authors.initials: L
authors.lastname: Li
authors.affiliation: The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P. R. China.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Feng
authors.affiliation: The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P. R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P. R. China. Electronic address: shenzhf@imm.ac.cn.
authors.forename: Zhufang
authors.initials: Z
authors.lastname: Shen
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D002478:Cells, Cultured; D020536:Enzyme Activators / Q000494:pharmacology*; D005941:Glucokinase / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008817:Mice, Mutant Strains; D009539:Nicotinic Acids / Q000494:pharmacology*; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: C000603790:6-(5-(3-fluorobenzyloxy)-2-propoxybenzamido)nicotinic acid; D001549:Benzamides; D020536:Enzyme Activators; D007004:Hypoglycemic Agents; D009539:Nicotinic Acids; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D005941:Glucokinase; D005947:Glucose
keywords: Glucose consumption; Hyperglycemia; Insulin secretion; Islet; Type 2 diabetes