Insulin Resistance - Treatment Options
THIAZOLIDINEDIONES
With Rosiglitazone and Troglitazone being withdrawn due to cardiac and hepatic concerns respectively, Pioglitazone remains the only player in this group at present. Thiazolidinediones improve insulin sensitivity in both liver and muscle. They augment insulin stimulated muscle glucose uptake and enhance basal and insulin mediated suppression of HGP. Improvement in glycaemia may contribute to improved beta cell function.
Both thiazolidinediones were shown to produce a 35% increase in insulin mediated muscle glucose disposal in T2DM patients using a euglycaemic insulin clamp. Treatment of T2DM with rosiglitazone almost completely reversed the severe impairment in IRS-1 tyrosine phosphorylation, and markedly increased PI-3 kinase activity. This closely correlated with improvement in muscle insulin sensitivity and muscle glycogen synthesis measured with euglycaemic clamp. The above mechanisms imply that thiazolidinediones may be effective in preventing/delaying progression of IGT to T2DM.
The thiazolidinediones also seem to enhance insulin secretion probably through increasing glucose uptake by the beta cell. Diabetologia. 1995 Jan;38(1):24-30.They have also been shown to preserve beta cell function in diabetic animal models. The beneficial effect of thiazolidinediones may partly be related to the favourable fat redistribution since this happens despite a consistent finding of weight gain! They reduce hepatic and visceral fat, while increasing subcutaneous fat. The effect on intramyocellular fat is controversial with studies for and against such an action. Thiazolidinediones seem to consistently lower the plasma FFA concentration by 25-35%. Diabetes Care. 2001 Apr;24(4):710-9. This reduction in free fatty acid levels may be brought about partly by improving insulin sensitivity and partly through suppression of TNF alpha expression in adipose tissue -which normally facilitates lipolysis- by thiazolidinediones. Diabetes Obes Metab. 2001 Aug;3 Suppl 1:S11-9. A direct protective effect of beta cells from lipotoxicity seems to be offered by glitazones in in vitro studies. Am J Physiol Endocrinol Metab. 2004 Apr;286(4):E560-7
Triglyceride accumulation in beta cells of pancreas causes in increase in fatty acyl coA levels with increased ceramide synthesis which increases NO resulting in beta cell apoptosis. It is proposed that improvement of triglyceride content in the pancreatic beta cells brought about by thiazolidinedione therapy in the rats might explain the decreased beta cell apoptosis with the possibility of preservation of pancreatic islet function for longer. J Biol Chem. 1998 Feb 6;273(6):3547-50. The increased proinsulin to insulin ratios, which correlates with beta cell dysfunction and is predictive of type 2 diabetes development, Am J Med. 2003 Apr 15;114(6):438-44. is also improved by thiazolidinediones. Diabet Med. 2004 Jun;21(6):568-76.
Both thiazolidinediones were shown to produce a 35% increase in insulin mediated muscle glucose disposal in T2DM patients using a euglycaemic insulin clamp. Treatment of T2DM with rosiglitazone almost completely reversed the severe impairment in IRS-1 tyrosine phosphorylation, and markedly increased PI-3 kinase activity. This closely correlated with improvement in muscle insulin sensitivity and muscle glycogen synthesis measured with euglycaemic clamp. The above mechanisms imply that thiazolidinediones may be effective in preventing/delaying progression of IGT to T2DM.
The thiazolidinediones also seem to enhance insulin secretion probably through increasing glucose uptake by the beta cell. Diabetologia. 1995 Jan;38(1):24-30.They have also been shown to preserve beta cell function in diabetic animal models. The beneficial effect of thiazolidinediones may partly be related to the favourable fat redistribution since this happens despite a consistent finding of weight gain! They reduce hepatic and visceral fat, while increasing subcutaneous fat. The effect on intramyocellular fat is controversial with studies for and against such an action. Thiazolidinediones seem to consistently lower the plasma FFA concentration by 25-35%. Diabetes Care. 2001 Apr;24(4):710-9. This reduction in free fatty acid levels may be brought about partly by improving insulin sensitivity and partly through suppression of TNF alpha expression in adipose tissue -which normally facilitates lipolysis- by thiazolidinediones. Diabetes Obes Metab. 2001 Aug;3 Suppl 1:S11-9. A direct protective effect of beta cells from lipotoxicity seems to be offered by glitazones in in vitro studies. Am J Physiol Endocrinol Metab. 2004 Apr;286(4):E560-7
Triglyceride accumulation in beta cells of pancreas causes in increase in fatty acyl coA levels with increased ceramide synthesis which increases NO resulting in beta cell apoptosis. It is proposed that improvement of triglyceride content in the pancreatic beta cells brought about by thiazolidinedione therapy in the rats might explain the decreased beta cell apoptosis with the possibility of preservation of pancreatic islet function for longer. J Biol Chem. 1998 Feb 6;273(6):3547-50. The increased proinsulin to insulin ratios, which correlates with beta cell dysfunction and is predictive of type 2 diabetes development, Am J Med. 2003 Apr 15;114(6):438-44. is also improved by thiazolidinediones. Diabet Med. 2004 Jun;21(6):568-76.