Prevention of type 2 diabetes mellitus at a preclinical phase with pharmacologic treatment has been gaining interest. Medications that have been proposed include acarbose, metformin, orlistat, antihypertensives, and the thiazolidinediones (TZDs). The pharmacologic prevention of complications of diabetes using pharmacologic means, or tertiary prevention, is beyond the scope of this discussion. The Study TO Prevent Non–Insulin-Dependent Diabetes Mellitus (STOP-NIDDM) is a double-blind, placebo-controlled, randomized trial with an intention-to-treat analysis evaluating high-risk persons with impaired glucose tolerance. The participants received either a placebo or acarbose 100 mg 3 times daily, an alpha-glucosidase inhibitor known to improve sensitivity to insulin and decrease postprandial hyperglycemia. Both groups also received instruction on weight reduction and exercise, and had a yearly meeting with a dietician. A total of 714 patients were allocated to the treatment arm, and 715 received placebo. The mean follow-up time was 3.3 years, and the primary endpoint was development of diabetes. Nearly one-quarter of patients randomized to acarbose discontinued treatment because of gastrointestinal side effects including flatulence, diarrhea, and abdominal cramping. Of the patients who completed the study, there was a 25% reduction in the risk of progression to type 2 diabetes for those who already had developed impaired glucose tolerance. Of note, the incidence of diabetes actually increased following the discontinuation of acarbose taken as part of this study.1 Correspondence that followed questioned whether the positive results merely reflected a delay in the progression of diabetes rather than an actual prevention.2 Metformin, a biguanide, is known to increase muscle tissue insulin sensitivity and decrease hepatic glucose production. Several studies have been published regarding the potential use of metformin to prevent type 2 diabetes mellitus, with the initial studies being limited by small samples and lack of data regarding adherence. A large, double-blind, randomized, controlled trial of 3234 patients with an intention-to-treat analysis compared the effectiveness of metformin, placebo, or “intensive” lifestyle modification in preventing the primary outcome of progression to diabetes based on 1997 American Diabetes Association (ADA) criteria. The mean follow-up period was 2.8 years, mean age 50.6 years, mean body mass index (BMI) 34, and mean HbA1c 5.91. As compared to placebo, metformin and intensive lifestyle modification reduced the incidence of diabetes by 31% and 58%, respectively. Metformin was less effective in patients with a lower baseline BMI and lower baseline fasting blood glucose, and was associated with an increased incidence of gastrointestinal adverse effects. The researchers concluded that both metformin and intensive lifestyle modification prevented or delayed progression to frank diabetes, with effects being similar across groups regardless of gender, race, ethnicity, or age.3 A recent review summarized the results of clinical trials thus far in answering the question of whether metformin prevented type 2 diabetes mellitus. The authors concluded that given the lack of long-term data and possibility of “masking disease” rather than “preventing disease,” more studies are required before practice changes are made.4 Recent research into cost-effectiveness has shown that the cost per quality adjusted life-year from a societal perspective was $8800 for the lifestyle intervention and $29,900 for the metformin intervention. The metformin treatment was not judged to be cost-effective in those older than 65 years of age.5 Thiazolidinediones are believed to decrease beta-cell apoptosis and increase formation of new beta cells, thereby increasing beta-cell mass and endogenous insulin production through a variety of mechanisms.6 Studies have shown that troglitazone, which was removed from multiple marketplaces in March 2000 secondary to liver toxicity, may reduce the vulnerability of beta cells to autoimmune destruction.7 The TRoglitazone In Prevention Of Diabetes (TRIPOD) study8 is a randomized, controlled trial that demonstrated protection from progression to type 2 diabetes in two-thirds of women who had recent gestational diabetes. Follow-up at eight months after discontinuation of troglitazone demonstrated continued protection from progression to diabetes.8,9 Additional studies are needed with other medications in this class that remain approved for use. Epidemiologic and pharmacologic studies have found a relationship between thiazide diuretics, beta blockers, and increased insulin resistance. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) may improve insulin resistance and glucose metabolism. A recent article in the Journal of the American College of Cardiology summarized data from 11 prospective trials.10 A significant reduction was found in the incidence of diabetes for new diabetes in persons taking an ACE inhibitor, ARB, or calcium antagonist.10 Many of the trials of pharmacologic prevention have had intriguing positive results worthy of further research. At the present time, however, they should be viewed as research in progress, and not considered as substitutes for aggressive lifestyle modification. ROLE OF GENETICS Several lines of evidence from twin and family studies suggest that the pathogenesis of type 2 diabetes mellitus includes a strong genetic component.11 Mapping the susceptibility genes that account for this risk has proved difficult. Only a minority of all persons with type 2 diabetes are believed to have a single-gene defect, such as maturity-onset diabetes of the young (mutated MODY gene), syndrome of insulin resistance (insulin receptor defect), and maternally inherited diabetes and deafness (mitochondrial gene defect).12,13 The majority of type 2 diabetes cases are believed to result from a complex interaction between genetic and environmental factors. This has made the aim of finding susceptibility genes difficult because of the contribution of multiple genes, the involvement of a wide variety of environmental factors, the lack of a clear mode of inheritance, and the presence of genetic heterogeneity.14 Despite these limitations, advances in biotechnology have provided significant data regarding the role of genetics in the etiology of type 2 diabetes. This is based on a large number of association studies using candidate gene variations and genome scans. These studies have enhanced our understanding of genes and their relationship to environmental factors, and have allowed the development of measures to prevent type 2 diabetes. A candidate gene is a gene believed to be associated with a particular disease based on either its position on a specific chromosome or its product(s). A large number of genes have been examined based on their function in insulin secretion or activity. Examples of these genes include the sulfonylurea receptor,15 the insulin receptor substrate-1 (IRS-1),16 and the peroxisome proliferator-activated receptor-gamma (PPAR-)17 genes. To date, these candidate genes, and other candidate genes shown to impact insulin resistance and diabetes, appear to have small effects on the risk of developing type 2 diabetes.12 Yen et al18 identified a common variant of the human PPAR-2 gene called Pro12Ala. Altshuler et al19 studied more than 3000 individuals and found a modest (1.25-fold) but significant (P = 0.002) increase in diabetes risk in the Pro12Ala gene variant group. Because this gene variant occurs frequently, it is believed to play a role in as many as 25% of persons with type 2 diabetes.19 Thus, PPAR- has become not only an attractive target in the treatment of diabetes but also a potential candidate for preventing it. Support for the role of PPAR- ligands in the prevention of type 2 diabetes was demonstrated in the TRIPOD study9 as mentioned earlier. Investigators have also been using the genome-wide scan approach and linkage studies to investigate the clustering of certain chromosomal regions among family members with type 2 diabetes. Hanis et al20 screened the human genome for markers of type 2 diabetes in Mexican Americans; the authors identified a susceptibility gene on chromosome 2q37 designated as NIDDM1. In 2000, Horikawa et al21 cloned a gene in the NIDDM1 region that encodes calpain-10 (CAPN10). Calpain plays a role in membrane fusion, hydrolyzes various proteins that participate in cellular signaling, and is also important for differentiation of preadipocytes to adipocytes.22 These facts raise the possibility that calpain modulates both insulin secretion and action.22 A large number of subsequent linkage studies have identified additional type 2 diabetes susceptibility loci on various chromosomes. These include 1q, 5q, 8p, 10q, 12q, and 20q.23 These loci contain susceptibility genes and are worthy of further investigation. As investigators continue to unravel the genetic code of diabetes mellitus, there continues to be interest in genes and cells as biomedics. Although primarily aimed at cancer, gene engineering and cell therapy appear to be attractive strategies for metabolic disorders that include diabetes. For type 1 diabetes, the transplantation of islet cells that are engineered to evade or suppress the recipient immune response may yield benefit.24 Principles of gene therapy focus mainly on the generation of sources of insulin-producing tissue that can be replenished, such as the destroyed or failing beta cells.25 The achievements of gene and cell therapy in type 2 diabetes are less evident, but seminal studies promise that this modality may be used to treat, and perhaps even prevent, the underlying causes of the disease.24 Targeting tissues such as muscle and fat with genes whose products promote insulin sensitivity and glucose uptake is another promising approach that does not carry with it the side effects often associated with pharmacologic agents currently in use.24 ROLE OF OXIDATIVE STRESS Even prior to the development of diabetes mellitus, hyperglycemia plays a role in altering cellular signaling and diabetic gene expression. Hyperglycemia leads to the production of reactive oxygen species (ROS), as described later in this section. Several lines of evidence have shown that ROS modulate various biological functions by stimulating transduction signals, some of which are involved in the pathogenesis of diabetes.26 Redox-sensitive signaling pathways have been shown to play an important role in the development, progression, and damaging effects on beta cells within the islets of the pancreas.27 Although not a model to prevent diabetes itself, hyperglycemia leads to glycation, a nonenzymatic binding of glucose to proteins leading to the formation of advanced glycation (glycosylation) end-products (AGEs)28 and tissue damage. Most AGEs are endogenous, but some are exogenous, being derived from foods or even tobacco.29 Increased glycation and build-up of tissue AGEs have been implicated in diabetes, its complications, and disease progression because they can alter enzymatic activity, decrease ligand binding, modify protein half-life, and alter immunogenicity.30 There is considerable interest in developing methods aimed at anti-glycation as a therapeutic approach to prevent the complications of diabetes as well as delay its progression. The polyol pathway described by Chung et al31 illustrates the cascade of events leading to the production of ROS and AGEs during hyperglycemia. Under hyperglycemic conditions, as much as 30% of the glucose is channeled into the polyol pathway,32 causing a substantial depletion of nicotinamide-adenine dinucleotide phosphate (NADPH), and thus a significant decrease in the glutathione (GSH) level and antioxidant capacity of the cell.31 The polyol pathway also converts glucose to fructose; because fructose and its related products are more potent nonenzymatic glycation agents than glucose itself, the flux of glucose through the polyol pathway increases AGE formation, thereby increasing oxidative stress.31 Evidence for the role of oxidative stress in the etiology of type 2 diabetes has been supported by various trials. Studies in both humans and rodents showed that dietary supplementation with antioxidants may decrease the risk of developing type 2 diabetes, reduce insulin resistance, and protect vascular endothelium function.33 In a population-based follow-up study, Salonen et al34 investigated whether low vitamin E status was a risk factor for developing type 2 diabetes. With diabetes assessed at baseline and at four years, the authors followed a random sample of 944 men 42-60 years of age who had no diabetes at baseline examination. Results revealed that low vitamin E levels were significantly associated with a 3.9-fold increase in the incidence of diabetes.34 Thus, additional research appears warranted. ROLE OF INFLAMMATORY AND IMMUNOLOGIC FACTORS In addition to oxidative stress, inflammatory and immunologic factors have also been linked to the development and progression of type 2 diabetes. Immunologic markers include autoantibodies to islet-cell cytoplasm (ICA)35 and glutamic acid decarboxylase (GADA).36 Even though these markers are present in the majority of persons with type 1 diabetes, they can occur at any age,37 and are present in up to 10-15% of subjects diagnosed clinically with type 2 diabetes.38 The United Kingdom Prospective Diabetes Study (UKPDS 25)39 reported that of those patients older than 55 at the time of being diagnosed with diabetes, 44% with ICA, 34% with GADA, and 5% with neither antibody required insulin therapy within 6 years (P < 0.0001). Among patients older than age 45 years at time of diagnosis, although BMI and HbA1c provided little predictive information on future insulin requirements, the positive predictive value of GADA (≥ 60 U/L) alone, or both GADA (≥ 20 U/L) and ICA (> 5 U/L) for insulin therapy, were 52% and 68%, respectively.39 In addition, Syed et al38 found that in a subset of patients with type 2 diabetes, there was a pronounced activation of the acute-phase response that may in part explain the defect in insulin secretion as well as insulin resistance seen in type 2 diabetes. Collectively, these studies are important because the use of autoantibodies and inflammatory markers could lead to the development of immunomodulatory therapeutic strategies that could be used to delay, or hopefully even prevent, diabetes and its complications.38 CONCLUSION Epidemiologic and familial studies have revealed the multifactorial aspect of diabetes. There continue to be promising data regarding the role of pharmacologic therapy not only to treat diabetes but also as a possible way to prevent it. In addition, progress in defining the genetic basis of type 2 diabetes will certainly accelerate our progress toward developing novel therapies to prevent and treat the disease. One must, however, keep in mind the influence that environment and lifestyle modifications have on the expression of these genes. Genes predisposing to type 2 diabetes might have been survival genes for our ancestors, helping them to store energy during long periods of starvation.40 However, when these genes are exposed to a sedentary lifestyle and high caloric intake typical to the Western world, they predispose to obesity and insulin resistance.40 Therefore, formulating a comprehensive strategy to prevent diabetes requires a better understanding of the role of genes in causing diabetes, as well as an appreciation of the effects of hyperglycemia and insulin resistance on generating oxidative stresses, increasing inflammatory substances, and depleting essential nutrients.