Toxicity to the Insulin-Secreting β-Cell

This chapter presents published research that indicates certain organic compounds are capable of toxicity to β-cells located in the islets of Langerhans in the pancreas. The result of this toxicity is the loss of insulin and the onset of hyperglycemia leading to a diabetic state. Because the incidence of diabetes in humans is increasing in many countries around the world, the mechanisms that trigger the disease must be identified and understood. From the results of the research presented in this chapter, it seems likely that the decline of insulin production and secretion caused by exposure to particular chemicals may be involved in the onset of diabetes. The Introduction to the chapter provides a brief overview of the common types of diabetes and provides references to published reviews which indicate that exposure to certain chemicals can damage the insulin-producing β-cells. This is followed by an introduction to the normal and abnormal morphology of the endocrine pancreas. Several hormones including insulin, glucagon, and somatostatin are produced in the islets of Langerhans. The interactions of these hormones including the production and release of insulin are examined. The processes of insulin synthesis and secretion are presented in some detail and clarified by the use of several diagrams. To begin the study of compounds known to damage the insulin-producing β-cells, it is important to note that the chemical structure of these agents is diverse. Thus, it seems reasonable to suggest that the mechanisms involved in damaging the insulin-producing cells are also different. To study this hypothesis, the results of mechanistic research from three different chemicals were examined. Alloxan, a reactive cyclic urea derivative, and streptozotocin (STZ), an N-methylnitrosourea derivative, are cytotoxic agents that destroy β-cells, whereas cyproheptadine (CPH), a diphenylmethylpyridine derivative with therapeutic activities, is an antihistamine and antiseratonin drug. CPH selectively inhibits the synthesis of insulin in β-cells. Exposure to any one of these agents in laboratory animals causes a loss of insulin resulting in hyperglycemia and the diabetic state. Alloxan, a reactive chemical, produces oxygen free radicals in amounts that overwhelm protective mechanisms in β-cells. STZ is cytotoxic because it is an alkylating agent and a producer of nitric oxide that is known to damage cells. Details of these actions are complex and the reasons for the β-cell selectivity of these cytotoxic agents are not completely clear at this time. In contrast, CPH is not cytotoxic but it induces diabetes in rodents due to a loss of insulin in β-cells because of inhibition of insulin synthesis. In vitro studies of the mechanism of this result does not appear to be in transcription of preproinsulin mRNA but in the initiation of translation. Of particular concern in CPH toxicity are results of animal experiments that indicate relatively small exposures to CPH in pregnant rats, resulting in adult offspring from treated animals to have twice the amount of insulin in the pancreas compared to control animals. However, a glucose tolerance test in the animals exposed in utero indicated that they were in a diabetic state whereas control animals were normal. This is a disturbing result that indicates fetal exposure to CPH (and possibly other drugs) during pregnancy may play a role in the onset of diabetes. There is indirect evidence that toxicity to β-cells in laboratory animals may also cause diabetic-like symptoms in exposed humans. The toxic alterations caused by CPH in isolated β-cells from laboratory animals have also been observed in β-cells obtained from human β-cells exposed to similar concentrations of CPH. It is believed there are environmental exposures to chemicals and viruses that trigger the onset of diabetes in humans who have the genetic pattern that allows the onset of the disease. Given that at this time there is a small number of compounds each with different chemical structures that are known to produce a diabetic state via different toxic mechanisms in animal studies. For obvious reasons, research on the identities and toxic mechanisms associated with diabetogenic chemicals must be continued.