UCSF DIABETES, ENDOCRINOLOGY & METABOLISM TRAINING PROGRAM FACULTY RESEARCH SUMMARIES

I am involved in clinical research projects related to pediatric diabetes. Some recent and on-going projects are described below.

Prevention of type 1 diabetes : I served as the Site Director for the Diabetes Prevention Trial-Type 1 (DPT-1), a multicenter NIH-sponsored trial in which oral or parenteral insulin was used in an attempt to delay or prevent type 1 diabetes in high-risk individuals. The NIH has since expanded this line of research to TrialNet, a multi-center research consortium that devises trials to delay or prevent the onset of type 1 diabetes in those at risk, or to prolong endogenous insulin secretion (the honeymoon phase) in those with new-onset disease. UCSF was selected as one of 14 national centers for this study, and I serve as the Principal Investigator and Clinical Director at this institution. In addition, I have collaborated with Drs.Bluestone, Masharani (UCSF) and Herold (Columbia) in evaluating the role of an anti-CD3 monoclonal antibody in prolonging the honeymoon phase in those with new onset type 1 diabetes. Our initial results from a phase 1 / 2 study were published in the N Engl J Med . We are continuing to follow these patients over time, and have launched a phase 2 study for new onset diabetes, evaluating the efficacy of antibody treatment with 2 courses, at 12 month intervals. We are also planning additional studies to evaluate the window of opportunity for such therapy, with a trial planned from 6 weeks out to 6 months from diagnosis, and the use of anti-CD3 plus exenatide, a glucagon-like peptide-1 agonist. In addition, I am principal investigator on a new multicenter trial to study the safety and efficacy of anti-thymocyte globulin on preserving beta cell function in new onset type 1 diabetes (sponsored by Immune Tolerance Network, NIAID).

Improving metabolic control for Latino children with type 1 diabetes : Patients from minority groups with diabetes have poorer metabolic control and are at higher risk for long-term complications and death. We have decided to focus on improving diabetes care for the Latino population, as they represent the fastest growing minority group in the USA, and currently constitute the second largest ethnicity in the country. We recently completed a study on the effect of group interventions on metabolic outcomes and diabetes education in this population. We are now initiating a study to determine the effects of bilingual / bicultural nurses as case managers for Latino families. We are also evaluating the effect of a glucometer with telephonic modem connection for this population, with the goal to increase data transmission and communication with the diabetes team .

Insulin pump therapy in children with type 1 diabetes : We have an on-going evaluation of ~140 children now managed on the insulin pump, characterizing both metabolic outcomes and perceived changes in quality of life. In addition, we have completed a prospective randomized study of toddlers with type 1 diabetes, comparing multiple dose insulin injection therapy versus insulin pump.

Development of diabetes following pediatric renal transplantation: We have an on-going cohort that is followed in conjunction with our pediatric nephrology group. We are evaluating the effect of various parameters on risk for post-transplant diabetes, including the choice of immunosuppressants.

Type 2 diabetes in pediatrics : This type of diabetes has been exploding in the pediatric population, commensurate with the increase in obesity and more sedentary lifestyle. In conjunction with Dr. Christian Vaisse, we have been developing a cohort to evaluate clinical phenotype and underlying genotype of children with obesity and type 2 diabetes. Also, I am site director for a study sponsored by the Glaser Foundation to determine the effect of metformin and/or lifestyle interventions on obese children with insulin resistance.

In addition, one area of new investigation for me is characterization of the nephrogenic syndrome of inappropriate antidiuresis. The pediatric endocrine group at UCSF was the first to describe this novel condition, in which activating mutations of the vasopressin type 2 receptor result in a clinical phenotype resembling the syndrome of inappropriate antidiuretic hormone secretion. In subsequent studies, we are evaluating additional patients; determining the natural course of the disease; evaluating therapeutic options; and exploring the effects of receptor mutations on trafficking and intracellular signaling.

Selected References

Herold KC, Hagopian W, Auger J, Poumain-Ruiz E, Taylor L, Donaldson D, Gitelman SE, Harlan D, Xu D, Zivin R, Bluestone JA. Effects of anti-CD3 mAb hOKT3 g 1(Ala-Ala) in patients with new onset Type 1 diabetes mellitus. N Engl J Med, 346: 1692-1698, 2002.

Herold KC, Bisikirska B, Gitelman SE, Masharani U, Hagopian W, Donaldson D, Rother K, Diamond B, Harlan D, Bluestone JA. A single course of anti-CD3 mAb hOKT3?1(Ala-Ala) results in improvement in insulin secretion and clinical parameters for at least 2 years after onset of Type 1 diabetes. Diabetes, 54(6):1763-9, 2005.

Feldman BJ, Rosenthal SM, Vargas GA, Fenwick RG, Huang EA, Matsuda-Abedini M, Lustig RH, Mathias RS, Portale AA, Miller WL, Gitelman SE. Nephrogenic syndrome of inappropriate antidiuresis. N Engl J Med 352: 1884-1890, 2005.

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