Effects On Cell Function

Along with insulin resistance, p-cell dysfunction is also a cardinal feature of type 2 diabetes. Data from the UKPDS and other studies suggest that p-cell function decreases with duration of type 2 diabetes in all treatment groups (13,36). Since PPAR-y is expressed in human islet endocrine cells, it is possible that thiazolidinediones may have direct effects on human pancreatic endocrine cells (37). Improvements in p-cell function after thiazolidinedione treatment may also be secondary to increased insulin sensitivity and concomitant decrease in hyperglycemia. There is growing evidence from several studies that thiazolidinedione therapy improves p-cell function (38-42). These studies have evaluated p-cell function using both surrogate measures and also direct measurements of p-cell function like intravenous glucose tolerance tests, hyperglycemic clamps with arginine stimulation, assessment of baseline high-frequency insulin pulsatility, and glucose-entrained insulin pulsatility. A surrogate measure of p-cell function is the ratio of proinsulin (PI) to immunoreactive insulin (IRI). An elevated ratio of PI to IRI is often present in type 2 diabetes and may reflect dysfunctional p-cell processing of the prohormone and associated reduced p-cell secretory capacity (38). Treatment with the thiazolidinediones is associated with a decrease in PI/IRI ratio suggestive of direct effects on the p cell (38,39). In a study using direct measures of p-cell function, although rosiglitazone treatment for 3 months in type 2 diabetic patients exerted no action on insulin secretion per se, it did improve glucose-entrained high-frequency insulin pulsatility, thereby suggesting an increased ability of the p cell to sense and respond to glucose changes within the physiological range (40). Improvements in p-cell function have also been demonstrated in the TRIPOD (Troglitazone In Prevention Of Diabetes) and the PIPOD (Pioglitazone In Prevention Of Diabetes) studies in Hispanic women with prior gestational diabetes and extremely high risk for progression to diabetes (41,42).

In the ADOPT study, ß-cell function (by the HOMA-S method) was determined in 4360 type 2 diabetic subjects who were randomized to either rosiglitazone, metformin or glyburide as initial monotherapy and evaluated for monotherapy failure (defined as a confirmed FPG level of > 180 mg/dL) (14). After 5 years, the cumulative incidence of monotherapy failure in the rosiglitazone group was 15%, compared to 21% with metformin and 34% with glyburide. In this study, although there was a durable and robust improvement in insulin sensitivity with rosiglitazone, effects on ß-cell function were less robust with the annual rate of decline in ß-cell function after 6 months being 2% in the rosiglitazone group compared to 6.1% in the glyburide group and 3.1% in the metformin group.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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