Insulin Resistance -
OTHER TREATMENT OPTIONS
Sulphonylureas:
Among the sulphonylureas, the third generation sulphonylurea (Glimiperide) seems to have a more favourable cardiovascular profile. Horm Metab Res. 1996 Sep;28(9):496-507. Glimiperide seems to improve glycaemia to similar levels as the second generation sulphonylureas despite lower insulinotropic activity.Diabetes Res Clin Pract. 1995 Aug;28 Suppl:S115-37. This is thought to imply extra-pancreatic effects of Glimiperide through favouring peripheral glucose uptake as well as by augmenting first phase insulin secretion. Pharmacotherapy. 2004 May;24(5):606-20.
The term Glucotoxicity has been coined to explain the beta cell failure as well as peripheral insulin resistance in type 2 diabetes. Sulphonylureas may partly exert their beneficial effect through improvement of glucotoxicity. Glucotoxicity implies chronic elevation of plasma glucose levels inducing insulin resistance and impairing beta cell function by local toxicity. High levels of glucose down-regulates the glucose transport system in the muscle while up-regulating glucose-6- phosphatase in the liver with increased hepatic glucose production, both contributing to insulin resistance at the respective sites. An ongoing study with Nateglinide should address the issue of postprandial glucose reduction and improvement in insulin resistance effects. The fact that glycaemic control did not produce statistically significant improvement in Cardiovascular outcomes in the UKPDS suggests that tackling the glycaemic abnormality is probably not the whole answer to insulin resistance management.
ACE Inhibitors:
ACE Inhibitors improve muscle blood flow and increase muscle glucose uptake (increase GLUT4 activity). FEBS Lett. 2004 Oct 22;576(3):492-7. They suppress brain sympathetic activity thus improving insulin sensitivity. They may have an effect on the tissue ACE demonstrated in pancreatic beta cells. Increasing the bradykinin and prostaglandins in the muscle has been shown to improve insulin sensitivity of muscle and this could be a possible mechanism. Diabetes. 1998 Apr;47(4):550-8 Counteracting the deleterious effects of Angiotensin II in the adipose tissue, and recruiting new adipocytes by facilitating adipocyte differentiation could be yet another mechanism of action of ACE inhibitors. Diabetes Metab. 2004 Dec;30(6):498-505.
Among the sulphonylureas, the third generation sulphonylurea (Glimiperide) seems to have a more favourable cardiovascular profile. Horm Metab Res. 1996 Sep;28(9):496-507. Glimiperide seems to improve glycaemia to similar levels as the second generation sulphonylureas despite lower insulinotropic activity.Diabetes Res Clin Pract. 1995 Aug;28 Suppl:S115-37. This is thought to imply extra-pancreatic effects of Glimiperide through favouring peripheral glucose uptake as well as by augmenting first phase insulin secretion. Pharmacotherapy. 2004 May;24(5):606-20.
The term Glucotoxicity has been coined to explain the beta cell failure as well as peripheral insulin resistance in type 2 diabetes. Sulphonylureas may partly exert their beneficial effect through improvement of glucotoxicity. Glucotoxicity implies chronic elevation of plasma glucose levels inducing insulin resistance and impairing beta cell function by local toxicity. High levels of glucose down-regulates the glucose transport system in the muscle while up-regulating glucose-6- phosphatase in the liver with increased hepatic glucose production, both contributing to insulin resistance at the respective sites. An ongoing study with Nateglinide should address the issue of postprandial glucose reduction and improvement in insulin resistance effects. The fact that glycaemic control did not produce statistically significant improvement in Cardiovascular outcomes in the UKPDS suggests that tackling the glycaemic abnormality is probably not the whole answer to insulin resistance management.
ACE Inhibitors:
ACE Inhibitors improve muscle blood flow and increase muscle glucose uptake (increase GLUT4 activity). FEBS Lett. 2004 Oct 22;576(3):492-7. They suppress brain sympathetic activity thus improving insulin sensitivity. They may have an effect on the tissue ACE demonstrated in pancreatic beta cells. Increasing the bradykinin and prostaglandins in the muscle has been shown to improve insulin sensitivity of muscle and this could be a possible mechanism. Diabetes. 1998 Apr;47(4):550-8 Counteracting the deleterious effects of Angiotensin II in the adipose tissue, and recruiting new adipocytes by facilitating adipocyte differentiation could be yet another mechanism of action of ACE inhibitors. Diabetes Metab. 2004 Dec;30(6):498-505.