SUGAR MGH

In the United States, approximately 1.5 million people are diagnosed with type 2 diabetes each year, and another 6.2 million are unaware they have the disease. There are 54 million Americans at risk of developing type 2 diabetes in their lifetime.

A person’s risk for developing type 2 diabetes is increased by certain genetic factors. Some of the genes associated with the disease have been shown to affect hormonal mechanisms required for the regulation of sugar levels. In our study, SUGAR MGH, we will investigate whether the efficacy of specific anti-diabetic drugs is dependent on which variation of the gene the research subject carries. We will be measuring the effects of the medications glipizide and metformin while examining genes associated with type 2 diabetes.

The study will enroll subjects at risk of diabetes or with diet-treated diabetes, and will monitor their response to the two anti-diabetic medications during two visits over one week. Each patient’s DNA will be genotyped for several variants thought to play a role in diabetes, and the reactions of people who carry different genotypes will be compared. With studies such as this we hope to improve our understanding of mechanisms of glucose regulation and how they differ from person to person, propose better diagnostic strategies, describe how newly identified genetic variants increase diabetes risk, discover new forms of treatment and possibly allow therapies to be tailored to the individual.

Some studies showing the association between type 2 diabetes and the genes we plan to study:

• Gloyn et al., Diabetes 2003;52:568-572
“Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes”
http://diabetes.diabetesjournals.org/cgi/content/full/52/2/568

• Florez et al., Diabetes 2004;53:1360-1368.
“Haplotype structure and genotype-phenotype correlations of the sulfonylurea receptor and the islet ATP-sensitive potassium channel gene region”
http://diabetes.diabetesjournals.org/cgi/content/full/53/5/1360

• Grant et al., Nat Genet 2006;38:320-323.
“Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes”
http://www.nature.com/ng/journal/v38/n3/full/ng1732.html

• Florez et al., NEJM 2006;355:241-250.
“TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program”
http://content.nejm.org/cgi/content/full/355/3/241

Some studies showing the effects of variation in these genes on glucose regulation:

• Nielsen et al., Diabetes 2003;52:573-577
“The E23K variant of Kir6.2 associates with impaired post-OGTT serum insulin response and increased risk of type 2 diabetes”
http://diabetes.diabetesjournals.org/cgi/content/full/52/2/573

• Florez et al., Diabetes 2004;53:1360-1368
“Haplotype structure and genotype-phenotype correlations of the sulfonylurea receptor and the islet ATP-sensitive potassium channel gene region”
http://diabetes.diabetesjournals.org/cgi/content/full/53/5/1360

• Saxena et al., Diabetes 2006;55:2890-2895
“Common single nucleatide polymorphisms in TCF7L2 are reproducibly associated with type 2 diabetes and reduce the insulin response to glucose in nondiabetic individuals”
http://diabetes.diabetesjournals.org/cgi/content/full/55/10/2890

• Florez et al., NEJM 2006;355:241-250.
“TCF7L2 Polymorphisms and Progression to Diabetes in the Diabetes Prevention Program”
http://content.nejm.org/cgi/content/full/355/3/241

A study showing that the effect of metformin treatment may be dependent on the variation of the gene the patient carries:

• Florez et al., Diabetes 2007;56:531-536
“Type 2 diabetes-associated missense polymorphisms KCNJ11 E23K and ABCC8 A1369S influence progression to diabetes and response to interventions in the Diabetes Prevention Program”
http://diabetes.diabetesjournals.org/cgi/content/full/56/2/531

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