Modulating DDAH/NOS Pathway to Discover Vasoprotective Insulin Sensitizers

Table 1

Insulin sensitizing agents, their mechanisms of action, and associated adverse events.

Insulin sensitizing agent	Mechanism of action	Adverse effect
Metformin	Inhibits mitochondrial respiratory chain complex 1, activates AMPK pathway, decreases hepatic glucose production, stimulates glucose uptake, reduces ADMA, and increases NO	Gastrointestinal discomfort
Troglitazone	PPAR gamma agonist, regulates glucose metabolism, improves endothelial function, and enhances insulin sensitivity	Increases cardiovascular risk, hepatotoxicity
Rosiglitazone	PPAR gamma agonist, regulates glucose metabolism, improves endothelial function, and enhances insulin sensitivity	Increases cardiovascular risk
Pioglitazone	PPAR gamma agonist, regulates glucose metabolism, upregulates DDAH expression, reduces ADMA, increases NO, and enhances insulin sensitivity	Increases cardiovascular risk, bladder cancer
Sulfonylurea	Bind to ATP-sensitive potassium channel on the membrane of insulin secreting cells, increase insulin release, suppress hepatic glucose production, and reduce breakdown and release of fatty acids	Increases cardiovascular risk, severe hypoglycemia
INT-747	FXR agonist, enhances insulin sensitivity, upregulates DDAH expression, and reduces ADMA	Unknown
GW4064	FXR agonist, enhances insulin sensitivity, upregulates DDAH expression, and reduces circulating ADMA	Unknown

AMPK = adenosine monophosphate activated protein kinase; ADMA = asymmetric dimethylarginine; NO = nitric oxide; PPAR = peroxisome proliferator-activated receptor; DDAH = dimethylarginine dimethylaminohydrolase; ATP = adenosine triphosphate; and FXR = farnesoid X receptor.