The Diabetic Beta-Cell

In type 2 diabetes, insulin production and secretion are deranged. The mechanisms are investigated in isolated islet cells from diabetic animals (Psammomys obesus and GK rats), in dynamic (perifusion) and static studies or with a novel system of adult islet culture developed in the laboratory. The study involves the role of key beta-cell intermediate metabolites, kinases and transduction proteins 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

DNA-related factors that regulate insulin gene expression in the beta-cell were studied and elements that mediate glucose regulated insulin transcription were identified. Most important the glucose-sensitive factor of the beta-cell that controls the synthesis of insulin has been identified by us. 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 identified a novel pathway by which glucose down-regulates its own transport in muscle and adipose cells, thus initiating a glucose -dependent vicious cycle in diabetics. Effort are 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. Novel molecules are synthesized in attempt to develop drugs design to counteract the hyperglycemia-induced down-regulation of glucose uptake in diabetics.

Genetics of Type 2 Diabetes

The etiology of type 2 diabetes is multifactorial, but genetics plays a major role in the progress of the disease. We collected a large cohort of patients with type 2 diabetes and their families. In collaboration with groups in the US, we are searching for genes that increase the risk for the disease.

Genetics of Diabetic Complications

Although recent studies have clearly demonstrated that the degree of metabolic control is a major determining factor in developing diabetic complications, there is ample data to indicate that genetic elements play an important role as well.  We are in the process of collecting DNA from a large number of patients with long-standing diabetes. Once completed, we will use this cohort to identify genetic risk factors associated with the development of the different diabetic complications.

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, Kir6.2, GCK and GLUD1 mutation analysis, as well as on search for additional genetic causes for this multigenic clinical syndrome.  In a separate project, we study the mechanism of increased beta-cell proliferation in focal HI lesions.

Stem Cells

Transplantation of surrogate pancreatic ß-cell is the ultimate way to cure diabetes. Supply of functional ß-cells remains the limiting factor for that procedure. To be able to produce quantities of such ß-cells, an understanding of all factors involved in directing stem cells to differentiate into ß-cells is required.   “Master genes” control the development and function of the ß-cell. They are responsible for committing progenitor cells to an endocrine lineage by modulating additional genes with precisely defined timing. ß-cell master genes are also responsible for the acquisition and maintenance of the ß-cell phenotype by controlling the expression of key metabolic enzymes involved in rendering the cell responsive to glucose.

The mode of action and down-stream elements of ß-cell master genes are studied in precursor and differentiated beta cells.

We study the regulation of beta-cell differentiation in human embryonic stem cells and try to identify the key signals required for endoderm and endocrine pancreas development. In addition, we try to develop protocols for efficient selection of the early pancreatic progenitors, expansion and induction of terminal beta-cell differentiation of these cells in vitro and in vivo.

Bone Disease

Bone loss and secondary osteoporosis are common complications of inflammatory conditions and systemic diseases. We have studied the mechanisms of bone loss in mouse and rodent models of inflammatory bowel disease and biliary cirrhosis. We have focused on the role of Interleukin 10 (IL-10) in bone physiology, and characterized the skeletal phenotype in IL-10 deficient mice. In a separate project we are studying the association between sequence variants in genes encoding for key proteins in bone such as the vitamin D receptor and estrogen receptors genes and bone mineral density in psotmenopausal and secondary osteoporosis. The association between estrogen receptor gene variants and other estrogen-related clinical syndromes such as coronary artery disease in males and females and dementia are also studied.

The NET (Neuroendocrine Tumor) Team

Recently, a multidisciplinary group of physicians with the goal providing improved care of patients with neuroendocrine tumors - the “NET team”- has been established. 

NET tumors include carcinoid and islet-cell tumors, malignant pheochromocytomas and medullary carcinoma of the thyroid.  The need for this venture emanates from the rarity of NETs and the consequent lack of experience with these diseases of most health care providers. 

The NET team consists of endocrinologists, oncologists, gastroenterologists, surgeons, an interventional radiologist, a nuclear medicine physician and a pathologist, all with interests regarding diagnosis, treatment and follow-up of patients with NETs.  The initial aims of the team are as follows:

- To establish an inter-departmental registry recording all NET patients being treated at Hadassah.

- To map out the existing expertise present at Hadassah for dealing with various aspects of NET patient management.  Examples are laboratory diagnostic procedures such as chromogranin A determinations, specialized nuclear medicine imaging modalities such as Octreoscans, MIBG scans, DOPA-PET scans; expert surgical expertise for pancreatic and liver procedures; various “cytoreductive” modalities such as hepatic chemoembolization, radiofrequency ablation and cryosurgery.

- To establish treatment protocols for NET patients.

- To devise clinical trials for NET patients.

- To meet periodically for updates on various aspects of NET patient management and case presentations.

- To engage in basic research projects relevant to NETs.

- To establish a NET patient support group, with relevant knowledge in lay terms in Hebrew to be available as a link at the Hadassah and the Israel Endocrine Society Web sites.