Clinical Activity

The medical staff deals with all aspects of general endocrinology, pediatric endocrinology, and diabetes; patient care is provided both within the in-patient unit of the Department, and as consultation services in the other departments of the Hadassah hospitals (Ein Kerem and Mount Scopus). Outpatient clinics in adult endocrinology and diabetes are held in both Hadassah hospitals, and in the Modi'in Clinics. As a new service, the Jerusalem diabetes clinics of Kupat Holim Meuhedet are organized by and run with participation of the staff of the Department. There exists close collaboration with the endocrine clinics of the Department of Pediatrics, and with the endocrinologists/diabetologists of all the Sick Funds of the Jerusalem area, to whom weekly consultation services are offered. The Endocrinology laboratories are divided into clinical service and research laboratories. The clinical service laboratory, which is fully computerized, uses frontline technology for assaying ?40 hormones, hormone intermediates, and other tests of interest in endocrinology, including molecular genetic tests, to cover the needs of the Hadassah hospitals as well as of outpatients. The clinical interests of the service encompass all aspects of general endocrinology, with special emphasis on diabetes. Thus, new approaches are employed for the induction of remission in new-onset NIDDM or in patients with secondary failure to oral agents; in genetic endocrine syndromes including neonatal hypoglycemia, MEN syndromes, VHL disease, etc; endocrine tumors of the gastrointestinal tract; malignant endocrine tumors; diagnostic procedures in Cushing's syndrome; inborn errors of steroidogenesis; and others.

Research Activity

The dominating research interests of the Department are in the field of diabetes, and the biology of the beta-cell.

The diabetic B cell. In type 2 diabetes insulin secretion and the maturation of the hormone are modified. The mechanisms are investigated in isolated islet cells from diabetic animals (Psammomys obesus and GK rats), studying them by conventional incubations and perifusions, or with a novel system of adult islet culture developed in the laboratory. The study involves the role of PKC and PKA in insulin production and release, analysis of the toxic effect of chronic hyperglycemia on beta-cell function in vivo and in vitro, regulation of beta-cell growth and apoptosis, and modification of proinsulin gene-specific transcriptional factors under glucotoxic conditions and in diabetes-prone animals.

Gene therapy in diabetes. We have studied the DNA-related factors that regulate insulin gene expression in the beta-cell, and identified the elements that mediate glucose stimulation of insulin transcription. Most important, we have discovered the glucose-sensitive factor of the beta-cell that controls the synthesis of insulin. Presently the regulation of this factor (PDX-1) and its mode of action are under intensive study. This will open the road for constructing artificial beta-cells; we have indeed obtained successful double-transfectants and shown that regulated insulin gene expression may be induced in heterologous cells like hepatocytes. Furthermore, the same factor may play a dominating role in inducing the development of stem cells into mature beta-cells; this will be the future of beta-cell replacement therapy in type 1 and type 2 diabetes.

The molecular control of glucose transport. A major cause of insulin resistance is chronic hyperglycemia. Our group has discovered a new physiological regulatory loop by which glucose down-regulates its own transport in muscle and adipose cells, thus initiating a vicious cycle in diabetics. Effort is made towards clarifying the mechanisms by which the effect of glucose on the transport system is mediated. Furthermore, we have discovered that some simple molecules up-regulate the glucose transport in the absence of insulin. Original molecules are synthesized in view of developing drugs that can counteract the hyperglycemia-induced down-regulation of glucose uptake in diabetics.

Genetics of Type 2 Diabetes. The etiology of diabetes is multifactorial, but genetics plays a large part. We have collected a large number of type 2 diabetes families, and in collaboration with groups in the US are attempting to identify genes that cause increased risk of disease, focusing on mutation analysis and association studies on candidate genes such as the Katp channel genes, endosulfine and NIDDM-1.

Genetics of Hyperinsulinism of Infancy. We have studied the genetic etiology of this disease and in doing so, obtained information relevant to beta-cell physiology. Current studies focus on SUR1 and Kir6.2 mutation analysis, endosulfine mutation analysis and mechanism of increased beta-cell proliferation in focal lesions.

Additional research projects include treatment of type 1 diabetes by immunomodulation and expansion of beta-cell mass, and studies on the genetic basis for inherited endocrine disorders.