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Taking advantage of their access to the very large population of patients with diabetes that attends the Joslin Clinic, and their relatives, the investigators of this section aim to unravel the etiology of diabetes and its late complications. The focus is on the genetic determinants, environmental risk factors and natural history of the various disease processes underlying the development of type 2 diabetes and late diabetic complications such as nephropathy and cardiovascular disease. This research primarily involves the observation of patients or their families, and the investigators use very sophisticated study designs and analytical methods of epidemiologic and human genetics research. To facilitate this research, large databases have been generated that contain, in addition to clinical observations, genetic and proteomic characteristics.
Krolewski Lab:
The major goal of this lab is to understand the mechanisms leading to the development of diabetic kidney disease in humans, and how genetic and environmental factors impinge on them. In addition, Dr. Krolewski’s lab examines genetic determinants of typical type 2 diabetes.
Current topics include:
The role of inflammation in the initiation of declining renal function in type 1 diabetes.
Mechanisms of renal function decline in patients with type 2 diabetes and normo-albuminuria.
Identification of genes contributing to proteinuria in types 1 and 2 diabetes.
Identification of genes contributing to declining renal function in types 1 and 2 diabetes.
Identification of a type 2 diabetes susceptibility gene on chromosome 20q.
Doria Lab:
This lab aims to find genes that regulate insulin sensitivity and are involved in the development of insulin resistance. To this end, Dr. Doria is investigating early-onset, autosomal-dominant type 2 diabetes - a subtype that is more strongly determined by genetic factors than common type 2 diabetes but, like the common form, is characterized by the presence of insulin resistance. During the past ten years, he has assembled a collection of 88 extended families with this subtype of diabetes. This unique resource is used for genome-wide linkage screens aimed at identifying genetic abnormalities contributing to this phenotype. Since insulin resistance is a potent cardiovascular risk factor, Dr. Doria is also engaged in the search for genes that regulate susceptibility to macrovascular complications in type 2 diabetes. He is assembling a large population of subjects with type 2 diabetes that have different degrees of coronary artery disease to be used for candidate gene and genome-wide association studies.
Laffel Lab:
This lab seeks to identify factors associated with optimal glycemic control in youth, in order to devise means to reduce acute and chronic complications of diabetes. The Laffel lab includes pediatric clinical researchers and behavioral scientists performing clinical and outcomes research. The group designs, implements and evaluates interventions aimed at overcoming barriers to adherence to diabetes management. This research group also studies the impact of stressful life events, including anxiety and depression at onset of diabetes and during the course of treatment, in order to identify and design timely interventions. Clinical research efforts also include the study of youth with type 2 diabetes and pre-diabetes with efforts to identify optimal treatments. The Laffel lab also designs and evaluates new technologies aimed at increasing blood glucose monitoring and improving glycemic control.
Five recent “highpoints”:
Discovered that early diabetic nephropathy, so called microalbuminuria, is a dynamic clinical outcome that regresses to normoalbuminuria in the majority of cases. NEJM 2003. However, one third of cases with microalbuminuria have a process of progressive renal function loss initiated, and this process can be diagnosed using serial measurements of serum cystatin C. JASN, 2005.
Discovered that two major phenotypes of diabetic kidney disease, abnormalities in urinary albumin excretion (proteinuria) and renal function (impaired renal function and ESRD), have significant genetic determinants and different susceptibility genes. Kidney Int., 2006.
Mapped genetic loci on 8p23 and 2q37 that together may account for type 2 diabetes in about 50% of families with early-onset disease and an autosomal-dominant pattern of inheritance. Efforts are underway to clone these diabetes genes. Diabetes, 2004; Ann. Hum. Genet, 2006.
Identified a haplotype in the gene encoding the fatty acid transporter CD36 that is associated with increased free fatty acid levels and increased risk of coronary artery disease in type 2 diabetes. Hum. Mol. Genet., 2004.
Designed and implemented a clinic-based, ambulatory intervention for youths 9-14 yrs old with type 1 diabetes for a multi-center clinical trial to improve glycemic control. J. Pediatr., 2003.
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