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Long-term complications significantly impair the health of people with diabetes. The risk of having a stroke or dying from heart disease, for instance, is two to four times greater in people with diabetes. Diabetes is also the leading cause of blindness in working-age adults.
More than 25 clinical trials are under way at any given time, ranging from studies of promising new drugs to those evaluating the impact of lifestyle changes such as weight loss and increased physical activity.
About the Clinical Research Center
The third floor of the Joslin Diabetes Center contains 8 outpatient procedure and exam rooms dedicated to clinical research on diabetes, its complications and related metabolic disorders. Four of these rooms house the General Clinical Research Center (GCRC), which supports NIH-sponsored investigator-initiated research protocols. The remaining four rooms serve as the Clinical Trials Unit (CTU), which supports industry-sponsored clinical trials. In addition, a nutrition office, a specimen processing lab and an administrative office are resources available for investigators utilizing the GCRC and the CTU. The GCRC and CTU are open Monday through Friday. The Joslin General Clinical Research Center and Clinical Trials Unit are dedicated to performing quality research safely and efficiently while simultaneously addressing the needs and concerns of each research subject.
The major focus of the research section is to elucidate the underlying pathobiology and genetic determinants of type 2 Diabetes Mellitus (T2D) and its complications, and to develop effective treatment strategies to prevent or delay the development of diabetes and vascular disease in high-risk individuals. The scope of the work includes both small physiologic studies and large NIH-funded multi-center trials. Investigators in the section collaborate extensively with basic research sections at Joslin and with investigators in the surrounding Harvard-affiliated teaching hospitals and other academic institutions.
Horton Lab:
Current studies include three NIH-funded projects: the Diabetes Prevention Program Outcomes Study (DPPOS), the LookAHEAD Study and a program-project grant entitled “Ambient Particles and Cardiac Vulnerability in Humans”, PI Dr. Diane Gold, Harvard School of Public Health (HSPH), aimed to evaluate the effects of air pollution on endothelial function in T2D.
In addition, the effects of exendin-4 (exenetide) are compared with those of glargine insulin on endothelial function before and after meal feeding in patients with T2D. We are also participating in a multi-national trial to determine the relationship between mean blood glucose and HbA1c over a wide range in various racial/ethnic populations, with the long-term goal of establishing a worldwide standard for the HbA1c assay that can be expressed in terms of average blood-glucose concentration. Finally, meal replacement/supplements that potentiate GLP-1 secretion and improve post-prandial glucose responses by enhancing insulin and suppressing glucagon secretion are being studied.
Goldfine Lab:
Physiologic and molecular determinants of T2D are evaluated in non-diabetic persons at risk for the development of the disease, with a focus on family history (familial risk) or obesity (acquired risk) to identify potential new targets for treating or preventing T2D. Subjects with and without diabetes are carefully phenotyped for insulin sensitivity and β-cell function, and tissues are obtained to evaluate protein and gene expression in collaboration with the Patti (CMP) laboratory.
Both insulin resistance and disordered β-cell function characterize typical T2D. However, recent evidence from the Kulkarni laboratory (CMP) and others indicates that insulin receptors and insulin signaling proteins are found within the β cells themselves, and that the insulin signaling pathway is functionally important for glucose sensing in rodents and in cultured cells. However, the role of insulin signaling in normal and diabetic human β cells is largely unknown. Preliminary studies in our lab show that elevated circulating levels of insulin can enhance the insulin-secretory response of the β cell to glucose in healthy persons. We hypothesize that dysfunctional insulin signaling at the level of the β cell may be one mechanism underlying blunted insulin secretion in T2D patients with insulin resistance. If so, this would suggest that insulin resistance and the insulin-secretory defect, previously considered to be two independent processes contributing to the pathogenesis of T2D, may be coupled.
Studies from the Shoelson laboratory (CMP) and others suggest that western sedentary lifestyle and diet activate the NF-κB inflammatory pathway, subsequently causing release of inflammatory molecules and mediators of disease, and directly or indirectly inhibiting insulin signaling. Furthermore, activation of NF-κB can be inhibited by salicylates. Our preliminary human studies demonstrate that salicylates can reduce fasting and post-load glucose, reduce fatty acids and C-reactive protein, and increase adiponectin in patients with T2D as well as in overweight non-diabetic persons. Three multi-center studies are now underway to evaluate targeting inflammation with salsalate, a salicylate with a safety profile more favorable than that of aspirin, to treat T2D, improve insulin resistance, or reduce cardiovascular plaque progression.
Five recent “highpoints”:
Using gene-expression profiling, discovered that the PPAR-γ agonist rosiglitazone leads to alterations in the expression of transcription factors: necdin in human adipose tissue and E2F4 in human adipose and muscle tissue. Diabetes, 2006.
In collaboration with Shoelson (CMP), Goldfine is leading multi-center trials to target inflammation with salsalate in order to lower glycemia in patients with T2D, to improve insulin sensitivity in patients with impaired glucose tolerance, and to reduce the progression of cardiovascular plaque in patients with coronary artery disease and metabolic syndrome, using novel imaging techniques of multi-detector computed tomographic angiography (MDCTA).
The DPP showed that intensive lifestyle intervention decreased the risk of progression from impaired glucose tolerance (IGT) to diabetes by 58%, compared with a risk reduction of 31% with metformin. Subsequently, we showed that the risk of progression to diabetes was related to both reduced insulin secretion and action, as well as to the intervention. Similarly, the incidence of developing Metabolic Syndrome (ATP III criteria) was reduced by both lifestyle intervention and metformin, with lifestyle having the greater effect. Additionally, markers of CVD risk were also significantly reduced by lifestyle modification. Ann. Int. Med., 2005; Diabetes Care, 2005.
Reported that the DPP-like lifestyle-intervention program in obese subjects results in highly significant improvements of endothelial-dependent brachial artery vasodilation and reduction of several markers of endothelial activation and inflammation. Diabetes Care, 2003.
In collaboration with investigators at the Harvard School of Public Health, determined that ambient air quality affects endothelial function in people with T2D. This is now being studied in greater detail as part of an NIH-funded program-project grant. Circulation, 2005.
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