What Strategy to Use to Prevent TDM in Subjects Genetically Predisposed to TDM Lifestyle Intervention Pharmacological Therapy or Both

It is now clear that lifestyle interventions including dietary modification and regular physical activity delay the development of T2DM in genetically predisposed individuals [several excellent reviews are available (22, 23, 152, 250, 396, 399)]. Large prospective trials (400-403), as well as a number of smaller ones [included in reviews by Norris et al. (396), Gillies et al. (22) and Jeon et al. (250)], have confirmed this notion. In the Diabetes Prevention Program (DPP), the largest of the lifestyle intervention trials (n = 3,234 nondiabetic persons with elevated IFG and IGT), a lifestyle-modification program aimed at having patients reduce their weight by at least a 7% and perform at least 150 min of moderate intensity physical activity per week, led to a 58% reduction in the progression to T2DM over an average follow-up of 2.8 years as compared with the placebo group (402). The mean weight loss at the end of the trial was rather modest (~3 kg) with a maximum weight loss of ~7 kg in the first year followed by a gradual regain thereafter. The weight loss achieved in the DPP appears to be an achievable goal for most patients, something that can be stimulated with simple measures such as the use of pedometers (404). The DPP also showed that lifestyle intervention could be quite cost-effective, as to prevent one case of diabetes over a period of 3 years, only 6.9 persons would need to participate in such a program.

In addition to lifestyle-intervention, a number of drugs used to treat obesity (405) and T2DM, including acarbose (406), metformin (402, 407) and thiazolidinediones [(408-411) and preliminary data from the ACT NOW trial using pioglitazone (Ralph De Fronzo, personal communication) (412)], all have been successful to prevent the development of T2DM in high risk populations, despite very different mechanisms of action. This is puzzling as it suggests different/overlapping insults being implicated in P-cell dysfunction over time and calls for the need to better define the underlying causes. Of note, in the DPP most of the impact of metformin could be attributed to the induction of weight-loss (413). For example, the 1.7-kg weight loss with metformin compared to the 0.3 kg gain with placebo alone explained 64% of the beneficial metformin effect on diabetes risk. Adjustment for weight, fasting insulin, proinsulin, and other metabolic factors combined explained 81% of the beneficial met-formin effect, but it remained nominally significant (p = 0.034) (413). On the basis of the important role of lipotoxicity in T2DM discussed so far in this chapter, the poorly understood and rather unspe-cific way that metformin appears to prevent the development of T2DM contrasts with the basic and clinical data on the impact of thiazolidinediones to restore dysfunctional adipose tissue back to health; in humans thiazolidinediones improve the expression of genes involved in lipid synthesis (344, 346,

414), restore adipocyte sensitivity to insulin and prevent excessive release of FFA to ectopic tissues (64, 331) (and likely the P-cell (148), although unproven in humans), increase the secretion of adiponectin - an effect with vast metabolic implications at the level of the liver (64, 337, 340, 345,

415), muscle (127), and vascular bed (341, 342) - and ameliorate the release of inflammatory adipok-ines from macrophages and adipose tissue linked to insulin resistance (66, 126) and atherogenesis (416). In addition to the prevention of T2DM, early use of pioglitazone may reverse common metabolic complications of patients with IGT and T2DM, such as NAFLD (64) or PCOS (417), and reduce subclinical inflammation ,418) and atherosclerosis ,419). Pioglitazone has also been reported to reduce the risk of stroke and recurrent myocardial infarction in subjects with established CVD (420-423), although for unclear reasons rosiglitazone paradoxically increases myocardial infarction in patients with T2DM (424, 425) , Clinical trials with thiazolidinediones also suggest that they are the most promising of the currently available pharmacological agents for the prevention of T2DM (408-411).

In summary, until we understand better the mechanisms at play for P-cell preservation, treatment strategies will remain rather empiric for the prevention of T2DM in high-risk subjects. Nevertheless, prevention of obesity with amelioration of FFA-induced insulin resistance and P -cell lipotoxicity (141) appear as the most logical targets, at least in obese individuals genetically predisposed to diabetes. Perhaps in the future early screening for P-cell lipotoxicity by means of an acute intravenous lipid challenge (426), or by other means, will offer a unique opportunity to identify those at the highest risk, but also with the greatest potential to benefit from early intervention. The benefit of early intervention has been recently suggested in a recent analysis of the DPP database, where higher insulin secretion and better insulin sensitivity at baseline were associated with a lower risk of progression to T2DM (427) . From a practical standpoint, we cannot remain passive as the epidemic of T2DM looms. While not systematically tested, it is not difficult to envision that a combined approach of early lifestyle and pharmacological intervention targeting those at the highest risk will be needed in the future to curve the epidemic of T2DM, likely the greatest public health problem of affluent societies of the twenty-first century.

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