Glucokinase activators in diabetes management.
Type 2 diabetes is a chronic metabolic disease that adversely affects both the quality and longevity of life. The disease is characterised by elevated blood glucose (hyperglycaemia) that is associated with microvascular complications and increased macrovascular risk. Existing oral agents, either alone or in combination, do not exhibit adequate or sustained glucose lowering efficacy in Type 2 diabetics. Consequently, there is an unmet medical need for improved antidiabetic agents which are both more effective at lowering glucose and which display sustained efficacy over a number of years. Such agents would allow present glycaemic treatment targets to be achieved with greater success. Glucokinase activators (GKAs) represent a novel class of glucose-lowering agents. Preclinical data supports the notion that these agents act to lower blood glucose through effects in both the liver and pancreas. It is predicted that this dual compartment mechanism of action of GKAs will translate to robust glucose lowering in diabetic patients. The potential benefits and risks associated with the pharmacological activation of glucokinase are evaluated. The status of GKAs in preclinical and clinical development is assessed are the future prospects of these agents.
Coghlan
Matthew
M
AstraZeneca Pharmaceuticals, Diabetes and Obesity Drug Discovery, Cardiovascular and Gastrointestinal Research Area, Mereside, Alderley Park, Macclesfi eld SK10 4TG, UK. matthew.coghlan@astrazeneca.com
Leighton
Brendan
B
D000818:Animals; D002318:Cardiovascular Diseases / Q000517:prevention & control; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D005941:Glucokinase / Q000378:metabolism*; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000627:therapeutic use*
D007004:Hypoglycemic Agents; D005941:Glucokinase