Grand challenges in diabetes.

The magnitude of the diabetes epidemic – from its macrovascular (including heart attacks, strokes, and peripheral vascular disease) and the microvascular complications of diabetes (including retinopathy, nephropathy, neuropathy, and disorders of the integument and bone) – cannot be underestimated. In the US alone, an estimated 25.8 million people have diabetes, primarily Type 2. In 2010, 1.9 million new cases were diagnosed in people age 20 or older, amounting to more than 3500 each day. One in three children born today will become diabetic, and there are 79 million people in the US alone who are pre-diabetic. Complications of diabetes are a major cause of mortality and morbidity. Each year, diabetes contributes to 224,000 deaths, 96,000 amputations, or 1 amputation every 10 min in the US; 44,000 begin treatment for kidney failure; 12,000–24,000 become blind; and the cost is becoming overwhelming. In 2007, the cost was $178 billion, of which medical expenditures was $116 billion, with the indirect costs from loss of productivity estimated at $58 billion. Globally in 2003, there were 194 million and this is expected to increase by 2025 to 333 million – a 72% increase. The hardest hit is Asia with an expected increase of 106%. To what can we attribute this explosion, clearly the diabetes explosion is following closely on the heels of the obesity pandemic. The LOOK AHEAD study has taught us that a healthy lifestyle can reduce the metabolic consequences of obesity (Wing et al., 2011), but it is naive to think that this will deal with the global problem. What is needed are efforts to involve the legislators at city, state, nationally, and globally to find novel approaches to stemming this tide. In the meanwhile, a greater in-depth probing of the mechanisms of surgical approaches to reduction of calorie intake should surely lead to novel therapies for medically altering this landscape and for reducing the need for expensive and brutal surgery to counter a social disaster. The essential component of lifestyle management of obesity and diabetes is a change in physical activity, which unfortunately is an anathema to most people and a leading cause of diabetes and obesity. We need innovative and creative, fun activities as surrogates to replace the traditional “exercise.” Physicians and health professionals should act as role models engaging in enjoyable physical activities with achievable goals and with social and physiological benefits. However, there clearly is a lesson to be learned from the fact that only about 30–40% of obese people develop type 2 diabetes although 80–90% of type 2 diabetics are obese. What affords certain people this protection? Clinical and genetic risk factors identified in the Malmo study for this susceptibility include (HR): time period for either men or women (1.74), a first degree family history of diabetes (1.65), current smoking (1.39), increased body-mass index (per 1 SD, 1.49), increased fasting or 1 h postprandial plasma glucose (per 1 SD, 1.51), increased diastolic blood pressure (per 1 SD, 1.16), increased triglycerides (per 1SD, 1.28), increased y-glutamyltransferase (per 1 SD, 1.10), increased alanine aminotransferase (per 1 SD, 1.37). So the question arises: “Are there no guaranteed risk predictors which need to be sought energetically, perhaps allowing an earlier window of opportunity in prevention of progression?” Genetic studies of predisposition to T2D have now unearthed a combination of the risk alleles in 11 SNPs, and there are MODY genes which transmit the condition as an autosomal dominant – yet we can only account for <0.5% of the predisposition genetically. We need to do better and make a concerted effort, particularly now that we have the human genome in hand. An alternate to behavioral and genetic approaches is to address the mechanistic aspects of the different forms of diabetes. In type 1 diabetes, we now have an understanding of the genetic predisposition to autoimmune destruction of the pancreatic beta cells, the role of precipitating events, and how it ultimately devolves around a loss of beta cell mass and failure of islet regeneration by islet neogenesis or replication While there are agents that enhance neogenesis from proto-differentiated stem cells resident in the pancreas such as INGAP, the appropriate agents to curb the vicious inflammatory autoimmune attack have thus far escaped discovery. The gap between genomic stem cells, which, although promising, have yet to fulfill their promise, and alternative strategies using bone marrow or adipose tissue derived stem cells should receive greater attention as prospective therapies (Power and Rasko, 2011). There is a need to recapitulate fetal ontogeny, but there are elusive critical factors. However, the demonstration that adult stem cells can be reprogrammed ex vivo and tailored to generate the specific cells of interest is very encouraging. Our particular interest in this area has been using plasmids containing the genes of interest and injecting these into muscle or skin by electroporation, thereby creating a stable reproducing form of the gene of interest and its products. Similar approaches are likely to yield rewarding new therapeutic options. Furthering the understanding of the genetics and role of autoimmune mechanisms in type 1 diabetes and the genetics of type 2 diabetes are therefore topics of particular interest.