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Science 307 (5708): 369-

Copyright © 2005 by the American Association for the Advancement of Science

A Surfeit of Suspects

Paula A. Kiberstis
Genetic Factors in Type 2 Diabetes: The End of the Beginning?
S. O'Rahilly, I. Barroso, N. J. Wareham
How Obesity Causes Diabetes: Not a Tall Tale
M. A. Lazar
Diabetes, Obesity, and the Brain
M. W. Schwartz and D. Porte Jr.
Type 2 Diabetes—a Matter of b-Cell Life and Death?
C. J. Rhodes
Mitochondrial Dysfunction and Type 2 Diabetes
B. B. Lowell and G. I. Shulman
See related STKE and SAGE KE material, Editorial, News story, Perspective, and Reports by Wisløff et al. and Fukuhara et al.

If human diseases were story lines for the popular television drama CSI, type 2 diabetes would be one of the toughest cases. The key evidence is elevated blood glucose, but the crime scene encompasses multiple organ sites--the pancreas, liver, skeletal muscle, fat, and brain--each of which supplies a long list of molecular suspects that may or may not be causally involved in the disease. Why is solving this case so important? The numbers say it all: The global incidence of type 2 diabetes is projected to nearly double to 300 million people by the year 2025, and many of those affected will be young adults. Successful strategies to halt this epidemic will require a better mechanistic understanding of how the disease arises.

In a series of Viewpoints, Science provides a sampling of the many exciting leads currently being pursued by researchers. O'Rahilly et al. (p. 370) discuss the suspects that have emerged from genetic studies of rare inherited forms of diabetes and what this information has revealed about susceptibility to the more common forms of the disease. A major contributing factor in the escalating rates of type 2 diabetes is the global increase in obesity rates. On p. 373, Lazar considers the link between these two epidemics from both evolutionary and biological perspectives, highlighting the important role of fat-derived hormones in glucose metabolism. In a related Report, an intriguing new hormone secreted by visceral fat is described by Fukuhara et al. (p. 426). Schwartz and Porte (p. 375) review the mechanisms by which the brain regulates body fat and glucose metabolism, following up on ideas initially proposed by Claude Bernard more than a century ago. Rhodes (p. 380) discusses the important role of pancreatic beta-cell mass in glucose homeostasis and postulates that the body's inability to secrete enough insulin in type 2 diabetes may be due in part to an aberrant increase in beta-cell apoptosis. Finally, Lowell and Shulman (p. 384) summarize the evidence implicating mitochondrial dysfunction in the pathogenesis of type 2 diabetes. The link between mitochondria and metabolic disease is a theme continued in a Report by Wisløff et al. (p. 418).

Additional molecular suspects are featured in Science Online's Signal Transduction Knowledge Environment (STKE) and Science of Aging Knowledge Environment (SAGE KE) ( In STKE, Zick discusses the mechanisms controlling the phosphorylation of insulin receptor substrate proteins and how these mechanisms could be subverted to cause insulin resistance, whereas Ikonen and Vainio consider the impact of plasma membrane lipid composition on insulin signaling. Holz and Chepurny review the signaling pathways by which the glucose-lowering hormone glucagon-like peptide 1 could stimulate an increase in beta-cell mass. In SAGE, Faustman et al. discuss the use of spleen-derived stem cells as a possible strategy for regenerating insulin-producing pancreatic islet cells.

Which of these suspects will ultimately be found guilty? Stay tuned.

The T-381C SNP in BNP gene may be modestly associated with type 2 diabetes: an updated meta-analysis in 49 279 subjects.
H. Choquet, C. Cavalcanti-Proenca, C. Lecoeur, C. Dina, S. Cauchi, M. Vaxillaire, S. Hadjadj, F. Horber, N. Potoczna, G. Charpentier, et al. (2009)
Hum. Mol. Genet. 18, 2495-2501
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