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- December 1, 2008 |
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"Scientific Update: Rosiglitazone in Perspective"Dr. Robin Buckingham (biography)
English - 2003-07-02 - 64 minutes
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Summary :
We now understand the major pathophysiological defects of type 2 diabetes to be insulin resistance and beta cell failure. Epidemiological data suggest that inflammatory factors predict the future development of type 2 diabetes. What is the link between these inflammatory factors and the underlying pathophysiology of the disease?
One hypothesis is that insulin resistance and compensatory hyperinsulinemia, in tandem with chronic systemic inflammation, might explain the elevated rate of beta cell apoptosis in type 2 diabetes. How could this hypothesis be tested? Two long-term outcome studies are currently underway to do this – the ADOPT and DREAM studies, which are using rosiglitazone, a drug which happens to be insulin-sensitizing, insulin-sparing as well as anti-inflammatory.
This presentation gives an in-depth review of data supporting the properties of thiazolidinediones as being consistent with those of agents most likely to reduce the rate of beta cell apoptosis, and thereby, the rate of deterioration of glycaemic control, including new data from diabetes prevention studies and the first evidence of the vascular-protective effects of these drugs.
Learning objectives :
The participant will review data supporting the properties of thiazolidinediones as being consistent with those of agents most likely to reduce the rate of beta cell apoptosis, and thereby, the rate of deterioration of glycaemic control:
- Epidemiological data suggest that the pre-diabetic insulin resistant state, and Type 2 diabetes itself, are characterized by chronic, low-grade systemic inflammation.
- Insulin resistance and compensatory hyperinsulinemia, in tandem with chronic systemic inflammation, might explain the elevated rate of beta cell apoptosis in Type 2 Diabetes.
- To test this hypothesis, reducing insulin resistance and plasma insulin, together with reducing systemic inflammation, should reduce the rate of beta cell apoptosis and the rate of deterioration of glycaemic control.
- The ADOPT and DREAM studies are 2 long-term studies currently underway to test this hypothesis using rosiglitazone, an insulin-sensitizing, insulin-sparing AND anti-inflammatory drug:
o It reduced serum CRP levels in type 2 diabetic patients (Haffner et al, Circulation 106: 679-684, 2002).
o It reduced serum CD40 ligand (CD40L) concentrations (Marx et al, Circulation 107: 1954-57, 2003). CD40 and CD40L are surface proteins found on activated platelets (Ruggeri, Nature Medicine 8: 1227-34, 2002). They are also found in the activation cascade between T-lymphocytes and macrophages (Libby, Nature 420: 868-874, 2002).
o It inhibited IFN-?-induced expression of chemokines IP-10, Mig and I-TAC (Marx et al. J Immunology 164: 6503-08, 2000), which are involved in the recruitment of T-lymphocytes to the area of inflammation on the vascular wall (Libby, Nature 420: 868-874, 2002).
o It limited the expression of proinflammatory cytokines such as IFN-?, in activated human T-lymphocytes (Marx et al. Circ Res 90: 703-710, 2002).
- The ability of troglitazone to prevent diabetes was seen in the recent DPP data presented at the 63rd ADA Meeting, although the average duration of treatment was only 9 months (Diabetes 52 (Suppl 1): A58, 251-OR, 2003).
- The TRIPOD Study, however, showed over a 4 year follow up period a significant reduction in incidence of diabetes in women who had had gestational diabetes (Buchanan et al Diabetes 51: 2796 – 2803, 2002). The protective action of troglitazone was associated was persistent at 8 months after the medication was stopped, suggesting some kind of re-programming of the destructive mechanism on beta cells.
- We now have the first evidence that rosiglitazone is vascular-protective, as it has been shown to reduce restinosis after coronary stenting in Type 2 diabetics (Choi et al. Diabetes 52 (suppl 1): A19, 82-OR, 2003).
- Data coming out of the 2-year RESULT Study (Rosiglitazone Early vs SULfonylurea Titration) show that the combination of rosiglitazone with glipizide provides better glycaemic control than escalating the dose of glipizide alone.
Bibliographic references :
Sample Publications (of >50)
Buckingham RE, Al-Barazanji KA, Toseland CDN, Slaughter M, Connor SC, West A, Bond B, Turner NC, Clapham JC. The PPARg agonist, rosiglitazone, protects against nephropathy and pancreatic islet abnormalities in Zucker fatty rats. Diabetes 47: 1326-1334, 1998.
Walker AB, Chatington PD, Buckingham RE, Williams G. The thiazolidinedione rosiglitazone (BRL 49653) lowers blood pressure and protects against impairment of endothelial function in Zucker fatty rats. Diabetes 48: 1448-1453, 1999.
Smith SA, Lister CA, Toseland CDN, Buckingham RE. Rosiglitazone prevents the onset of hyperglycemia and proteinuria in the Zucker Diabetic Fatty (ZDF) rat. Diabetes, Obesity & Metabolism 2: 363-372, 2000.
Yue Y-I, Chen J, Bao W, Narayanan PK, Bril A, Jiang W, Lysko PG, Gu J-L, Boyce R, Zimmerman DM, Hart TK, Buckingham RE, Ohlstein EH. In vivo myocardial protection from ischemia/reperfusion injury by the peroxisome proliferator-activated receptor-g agonist rosiglitazone. Circulation 104: 2588-2594, 2001.
Carpentier A, Taghibiglou C, Leung N, Szeto L, Van Iderstine S, Uffelman K, Buckingham R, Adeli K, Lewis GF. Ameliorated hepatic insulin resistance is associated with normalization of microsomal triglyceride transfer protein (MTP) expression and reduction in very low density lipoprotein assembly and secretion in the fructose-fed hamster. J Biol Chem 277: 28795-28802, 2002.
Scheuermann-Freestone M, Madsen PL, Manners D, Blamire AM, Buckingham RE, Styles P, Radda GK, Neubauer S, Clarke K. Abnormal cardiac and skeletal muscle energy metabolism in patients with Type 2 diabetes. Circulation (in press).
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