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Diabetes Therapy Individualized Using Genetics

Posted: Tuesday, April 27, 2010

Advances in the genetics of Type 2 diabetes have provided a foundation for individual treatment strategies, which should be a continuing goal of research, according to a consensus statement from diabetes specialists.

Understanding of the heterogeneity of Type 2 diabetes has yet to reach a level that can guide therapy, but by building on existing knowledge, research initiatives can progress toward therapy tailored to the patient, the panel concluded.

Robert J. Smith, MD, of Brown University in Providence, R.I., and co-authors wrote, "As we move forward, we should continue to incorporate these and additional clinical observations with new data on the physiology and genetics of diabetes to assess the determinants of glycemic response to treatments in the larger Type 2 diabetes mellitus population."

The consensus conference was endorsed by the Endocrine Society and the American Diabetes Association.

Clinicians and scientists have long recognized the heterogeneous nature of Type 2 diabetes, but their ability to examine the underlying mechanisms is fairly recent.

Technologic advances have led to the recognition that a variety of clinical, genetic, behavioral, and socioeconomic factors might influence diabetes' development, progression, and response to therapy, the group wrote.

Diabetes pathophysiology also exhibits heterogeneity. Contributors to the heterogeneity include multiple pathways that can lead to insulin insufficiency and the abnormalities that precede Type 2 diabetes (such as impaired fasting glucose and impaired glucose tolerance). "Abundant data support the existence of pathophysiological subgroups within Type 2 diabetes mellitus, including evidence that the prevalence of diabetes and its precursor states may vary significantly by gender, ethnicity, and age," the authors wrote.

"In addition, the fact that nearly 25% of all patients diagnosed with Type 2 diabetes mellitus are not insulin resistant at diagnosis strongly supports distinct pathophysiological phenotypes of potentially different therapeutic requirements." The heterogeneity extends to the genetics and molecular basis of Type 2 diabetes, as well.

Insulin secretion and cellular responses to insulin are mediated by a variety of proteins and molecules that scientists have identified over several decades.

Variations in the expression or function of these proteins and molecules "undoubtedly represent important determinants of Type 2 diabetes mellitus heterogeneity via effects on beta-cell growth and development, insulin secretion, or changes in insulin responsiveness in specific or multiple tissues," the authors wrote.

Improved genotyping technology and the introduction of genome-wide scanning strategies have helped lead to the identification of more than 20 loci associated with Type 2 diabetes, they added.

In fact, more than two dozen disorders involve single-gene alterations that result in abnormal glucose homeostasis that overlaps features of Type 2 diabetes.

Existing therapies for Type 2 diabetes clearly do not provide similar control in every patient. However, the association between therapeutic response and specific variations in identifiable patient subgroups remains virtually unexplored.

"Currently, the most powerful demonstration of the value of using specific genetic subtypes to individualize therapy comes from identification of monogenic forms of diabetes," the consensus panelists wrote.

"Subgroups of diabetes defined by mutations in specific genes have been shown to be extremely responsive to some glucose-lowering therapies but not to others."

The panel concluded the statement with recommendations aimed at improving understanding of the heterogeneity of diabetes. The recommendations include:

    * Analyze existing data to identify associations between phenotypic and genotypic measures and glycemic control.
    * Expand existing diabetes registries and design new ones.
    * Develop clinical trials that specifically address heterogeneity of response to therapy.
    * Develop more accurate and efficient means to measure biomarkers of Type 2 diabetes.
    * Expand basic research.

Source: http://www.diabetesincontrol.com/index.php?option=com_content&view=article&id=9211&catid=53&Itemid=8, Smith RJ, et al "Individualizing therapies in Type 2 diabetes mellitus based on patient characteristics: what we know and what we need to know." J Clin Endocrinol Metab. 2010; DOI:10.1210/jc.2009-1966.