Israel Medical Association Journal

The 50th anniversary of the Israel Diabetes Association this year is a time less for celebration than for concern. The prevalence of diabetes is rapidly and alarmingly increasing in Westernized and developing countries around the world. Unfortunately, the majority of patients with diabetes do not meet their treatment goals – i.e., glucose, blood pressure or lipid levels. Moreover, our clinical experience and large longitudinal studies have taught us that the mean glucose levels of diabetic patients tend to increase over the years regardless of their treatment modalities. The appropriate answer to these somewhat frustrating data is that the medical community responsible for the integrated health of our diabetic patients – namely, physicians, researchers, nurses and dieticians – must use its combined resources and available therapeutic tools to optimize treatment for these patients. We should also deepen our understanding of the mechanisms underlying the various forms of diabetes and its complications in order to devise more efficient preventive measures for this prevalent devastating chronic disease.

This issue of IMAJ dedicated to diabetes provides some glimpses into these approaches. It contains relevant clinical management debates such as how and when insulin therapy should be instituted and which antihypertensive drugs are more appropriate in the treatment of diabetic nephropathy; a current state-of-the-art review of gestational diabetes as well as how to recognize and manage the diabetic Charcot foot. It exposes the reader to modern prevention strategies against type 1 and type 2 diabetes, to the search for alternative insulin-producing tissue, to advanced understanding of diabetic dermopathy, and more. It also includes selected abstracts of ongoing studies to be presented at the 2004 annual meeting of the Israel Diabetes Association. Most of all, the high quality of the clinical and basic research presented herein strengthens our hope for a better future for our diabetic patients.

Micha Rapoport MD (Guest Editor)

Department of Internal Medicine C and the Diabetes Service, Assaf Harofeh Medical Center, Zerifin, Israel

Editorial Committee

Hilla Knobler MD (Debate Editor)

Eleazar Shafrir PhD

Efrat Wertheimer MD PhD

Since both major forms of diabetes involve inadequate function of pancreatic beta cells, intensive research is ongoing to better understand how beta cells perform their complex role of secreting the hormone insulin in response to physiologic needs. Identification and characterization of pancreatic transcription factors has revealed that they play a crucial role not only in maintenance of mature beta-cell function but also at multiple stages in pancreatic development. Furthermore, recent reports have revealed their potential to convert non-beta cells into insulin-producing cells, which in some cases can function to ameliorate diabetes in experimental animals. The ability to translate these successes to the clinic will require a detailed mechanistic understanding of the molecular basis of action of these proteins. Specific gene regulation in beta cells involves the action of multiple transcription factors recruited to the promoter and functioning synergistically to activate transcription, in part through recruitment of co-activator proteins and components of the basal transcriptional machinery. In addition, the process involves modification of chromatin structure, the details of which are beginning to be elucidated. Our ability to modulate gene expression patterns may lead to developing ways to provide an unlimited supply of functional beta cells for transplantation, permitting a dramatic improvement in therapeutic options for diabetes.

Type 1 diabetes mellitus is caused by an autoimmune destruction of pancreatic islet beta cells, leading to insulin deficiency. Beta-cell replacement is considered the optimal treatment for type 1 diabetes, however it is severely limited by the shortage of human organ donors. An effective cell replacement strategy depends on the development of an abundant supply of beta cells and their protection from recurring immune destruction. Stem/progenitor cells, which can be expanded in tissue culture and induced to differentiate into multiple cell types, represent an attractive source for generation of cells with beta-cell properties: insulin biosynthesis, storage, and regulated secretion in response to physiologic signals. Embryonic stem cells have been shown to spontaneously differentiate into insulin-producing cells at a low frequency, and this capacity could be further enhanced by tissue culture conditions, soluble agents, and expression of dominant transcription factor genes. Progenitor cells from fetal and adult tissues, such as liver and bone marrow, have also been shown capable of differentiation towards the beta-cell phenotype in vivo, or following expression of dominant transcription factors in vitro. These approaches offer novel ways for generation of cells for transplantation into patients with type 1 diabetes.