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- May 16, 2008 |
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"Early combination therapy in type 2 diabetes: targeting insulin resistance and beta-cell dysfunction"Prof. John Nolan (biography)
English - 2003-08-26 - 25 minutes
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Summary :
Type 2 diabetes is a complex metabolic disease with major cardiovascular complications. The rapid increase in the prevalence of obesity and type 2 diabetes, with their complications, is a global health problem in terms of health expenditure and human cost. 'Diabesity' is increasingly used to describe the syndrome of diabetes and its associated complications that typically present as the Metabolic- or Insulin Resistance- Syndrome, including obesity, glucose intolerance, dyslipidaemia, hypertension and early atherosclerosis.
While the evolution of type 2 diabetes can be viwed as gradual progression of hyperglycaemia, from normal glucose tolerance (NGT), through impaired fasting glucose/impaired glucose tolerance (IFG/IGT) to frank diabetes, the syndrome is better viewed as a continuum of several metabolic processes. The microvascular complications of diabetes (retinopathy, nephropathy and neuropathy) correlate directly with glucose concentrations in the diabetic range (> 7 mM). However, it is increasingly recognized that the risk for macrovascular complications begins to increase at much lower concentrations in the pre-diabetic range (> 5 mM), including IFG and IGT, when there is evidence of significant endothelial dysfunction and insulin resistance is the predominant abnormality.
The pathophysiology of diabetes development and progression is based on two main metabolic abnormalities: insulin resistance and impaired pancreatic beta-cell function. Studies in the earliest phase of pre-diabetes have shown that insulin resistance is the predominant early abnormality, even in lean individuals who later progress to type 2 diabetes. Subtle defects in pancreatic beta-cell function become evident once IGT begins and are characterized by blunted early-phase insulin secretion and a late hyperinsulinaemic response. Once diabetes is established, insulin secretion is more disturbed with fasting hyperinsulinaemia, almost complete loss of the early-phase insulin response and blunted late response to glucose or meals. The cellular and molecular mechanisms of insulin resistance and beta-cell dysfunction remain imcompletely understood. However, the pathologies of these two defects appear to be interlinked, possibly through adverse effects of hyperglycaemia (glucotoxicity) and/or elevated free fatty acids (lipotoxicity) on insulin sensitivity and beta-cell function. This suggests that treatment to improve insulin sensitivity may also counter the gradual loss of beta-cell function that characterizes the progression of type 2 diabetes. This is supported by results from the TRIPOD study, where treatment of subjects at high risk of developing type 2 diabetes with an insulin-sensitizing agent could also preserve beta-cell function and delay or prevent the onset of type 2 diabetes.
Interventions is diabesity throughout its long evolution are best tailored to the pathophysiology of the syndrome. Early combination of treatments to bring glucose levels as close to normal as possible are likely to provide the best outcomes (particularly in relation to microvascular disease). Experience has also shown that multi-target interventions- addressing hyperglycaemia, beta-cell dysfunction and elements of the Insulin Resistance Syndrome, such as dyslipidaemia, hypertension and the pro-atherosclerotic state- are likley to provide the best protection against long term complications, and prospective trials support this early aggressive approach.
Learning objectives :
The participant will review the pathophysiology and evolution of type 2 diabetes and learn about treating the patient at different stages of the disease.
Bibliographic references :
Bergman RN, Phillips LS, Cobelli C. "Physiologic evaluation of factors controlling glucose tolerance in man: measurement of insulin sensitivity and beta-cell glucose sensitivity from the response to intravenous glucose."
J Clin Invest. 1981 Dec;68(6):1456-67.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7033284&dopt=Abstract
Bonadonna RC, De Fronzo RA. "Glucose metabolism in obesity and type 2 diabetes." Diab Metab. 1991 May;17(1 Pt 2):112-35.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1936466&dopt=Abstract
Buchanan TA, Xiang AH, Peters RK, Kjos SL, Marroquin A, Goico J, Ochoa C, Tan S, Berkowitz K, Hodis HN, Azen SP. "Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk hispanic women."
Diabetes. 2002 Sep;51(9):2796-803.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12196473&dopt=Abstract
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