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- December 1, 2008 |
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"Prevention of Type 2 Diabetes: Saving the Pancreatic B-cell"Prof. Thomas A. Buchanan (biography)
English - 2003-01-22 - 85 minutes
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 | (26 slides) |
 | (15 slides) |
Summary :
The epidemic of diabetes is occurring at three levels: positive energy balance, insulin resistance and loss of beta cell mass/function. Positive energy balance leads to obesity, and whether an obese person becomes insulin resistant depends on where their fatty acids accumulate and get metabolized. To the extent that fatty acids are spilled over from adipose tissue into liver and muscle, insulin signaling can be blocked in those tissues. In addition to this it’s been recently discovered that adipose tissue is an important endocrine organ which makes peptides that talk to liver and muscle and can block insulin signaling through some of the same pathways as fatty acids block insulin signaling. Hormones such as TNF-α, resistin and adiponectin are some examples. A lot of the variability in whether obese people become insulin resistant may be genetically determined. Finally, it depends how good the beta cells are. If a person has inherited robust beta cells, they will just make as much insulin as required, in spite of insulin resistance and as such, although the person may not develop diabetes, he/she might develop the other complications associated with insulin resistance. People with weak beta cells develop what’s probably a loss of beta cell mass and a loss of beta cell function, which leads to the hyperglycemia called diabetes. One could therefore go down this list and say there are three ways to prevent diabetes: you could improve the energy balance problem and prevent obesity, and this would reduce the incidence of type 2 diabetes. Another strategy is to uncouple obesity from insulin resistance, where people become obese, but they partition their fat back out of liver and muscle and put it into adipose cells and/or block signaling of the peptides from adipose tissue to liver and muscle. The third way is to get people whose beta cells are failing and get them to grow new beta cells or give them new beta cells. This presentation will focus on the middle paradigm which is uncoupling insulin resistance using a thiazolidinedione drug, troglitazone, which we use as a clinical research tool with people who are obese and insulin resistant who have failing beta cells, to uncouple their obesity from insulin resistance, and we will see how this also preserved their beta cell function.
Learning objectives :
- Troglitazone reduced the incidence of diabetes by 55% in high-risk Hispanic women
- Protection from diabetes required an increase in insulin sensitivity and was greatest in women who had the largest reduction in B-cell requirements ("B-cell rest")
- Women who were protected during the trial remained protected eight months later and had stable B-cell function over a 54-month period
- Reducing secretory demands placed on B-cells by chronic insulin resistance preserves B-cell function and delays or prevents Type 2 diabetes
- Intervention could be done as early as at the stage of impaired glucose tolerance, or when diabetes is found by doing yearly OGTTs. Stabilization of beta cell function was possible at both time points, but function was stabilized at a lower level when intervention was withheld until diabetes was first detected.
- There are 2 ongoing studies with TZDs. The PIPOD Study is looking at the stability of glucose levels and B-cell function during four years of pioglitazone treatment in women who completed TRIPOD. The DREAM study is looking at the effect of rosiglitazone and ramipril separately and in combination on diabetes rates in adults with impaired glucose tolerance.
- With high-risk people, the best intervention is diet and exercise, with serial glucose testing. If glucose concentrations continue to rise, consider pharmacological treatment either before diabetes or in the beginning of diabetes to achieve a target A1c (probably below 6%, and without stimulating insulin secretion)
Bibliographic references :
Prevention of Type 2 Diabetes: Saving the Pancreatic B-cell
Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk hispanic women.
Buchanan TA, Xiang AH, Peters RK, Kjos SL, Marroquin A, Goico J, Ochoa C, Tan S, Berkowitz K, Hodis HN, Azen SP.
Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, California 90033, USA. buchanan@usc.edu
Type 2 diabetes frequently results from progressive failure of pancreatic beta-cell function in the presence of chronic insulin resistance. We tested whether chronic amelioration of insulin resistance would preserve pancreatic beta-cell function and delay or prevent the onset of type 2 diabetes in high-risk Hispanic women. Women with previous gestational diabetes were randomized to placebo (n = 133) or the insulin-sensitizing drug troglitazone (400 mg/day; n = 133) administered in double-blind fashion. Fasting plasma glucose was measured every 3 months, and oral glucose tolerance tests (OGTTs) were performed annually to detect diabetes. Intravenous glucose tolerance tests (IVGTTs) were performed at baseline and 3 months later to identify early metabolic changes associated with any protection from diabetes. Women who did not develop diabetes during the trial returned for OGTTs and IVGTTs 8 months after study medications were stopped. During a median follow-up of 30 months on blinded medication, average annual diabetes incidence rates in the 236 women who returned for at least one follow-up visit were 12.1 and 5.4% in women assigned to placebo and troglitazone, respectively (P < 0.01). Protection from diabetes in the troglitazone group 1) was closely related to the degree of reduction in endogenous insulin requirements 3 months after randomization, 2) persisted 8 months after study medications were stopped, and 3) was associated with preservation of beta-cell compensation for insulin resistance. Treatment with troglitazone delayed or prevented the onset of type 2 diabetes in high-risk Hispanic women. The protective effect was associated with the preservation of pancreatic beta-cell function and appeared to be mediated by a reduction in the secretory demands placed on beta-cells by chronic insulin resistance.
Diabetes 2002 Sep;51(9):2796-803
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