Can thiazolidinediones delay disease progression in type 2 diabetes?
BACKGROUND
Type 2 diabetes results from increasing insulin resistance coupled with progressive loss of beta-cell function. Further deterioration of beta-cell function is associated with progression of diabetes and the potential development of microvascular and macrovascular complications.


METHODS
This review examines current knowledge of beta-cell function and uses this information to assess how the results of ongoing trials could increase our understanding of disease progression and potential interventions. Data were derived from a Medline search using the search terms 'beta-cell dysfunction', 'IGT', 'thiazolidinediones', 'metformin', and 'sulfonylurea'.


RESULTS
The mechanisms that underlie beta-cell dysfunction are complex and most likely involve the interplay of a range of factors that reduce both beta-cell mass and secretory function. These include detrimental effects associated with hyperglycemia itself, elevated free fatty acids, and inflammatory responses linked to adipocyte-derived cytokines, with apoptosis a key underlying mechanism. Early intervention with treatments that address these defects, and preserve beta-cell function while improving insulin sensitivity, may delay disease progression in patients with type 2 diabetes and also prevent the development of diabetes in 'at-risk' individuals. Two of the studies examining the effects of interventions on development and progression of diabetes that are due to report shortly are ADOPT (A Diabetes Outcome Progression Trial), comparing a thiazolidinedione, metformin and a sulfonylurea in patients with type 2 diabetes not previously treated with oral hypoglycemic agents, and DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication), assessing the effects of a thiazolidinedione and an angiotensin-converting enzyme inhibitor in subjects with impaired glucose tolerance and/or impaired fasting glucose.


CONCLUSIONS
Although we do not have a full understanding of the mechanisms driving progression of type 2 diabetes, there is growing evidence that we may be able to modulate them and thereby improve patient outcomes.
Leiter
Lawrence A
LA
Department of Medicine, University of Toronto, St. Michael's Hospital, Toronto, ON, Canada. leiterl@smh.toronto.on.ca
D048909:Diabetes Complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology; D016239:MEDLINE; D008297:Male; D013453:Sulfonylurea Compounds / Q000627:therapeutic use*; D045162:Thiazolidinediones / Q000627:therapeutic use*; D016896:Treatment Outcome
D007004:Hypoglycemic Agents; D013453:Sulfonylurea Compounds; D045162:Thiazolidinediones; C089946:2,4-thiazolidinedione