Perspectives in Diabetes Hyperproinsulinemia and Amyloid in NIDDM Clues to Etiology of Islet p-Cell Dysfunction?

Impaired islet function is a feature of non-insulindependent diabetes mellitus (NIDDM), which is manifested in part by disproportionate proinsulin release. A disproportionate increase in proinsulin also occurs in insulinomas, suggesting that enhanced proinsulin release results from an increase in synthesis and premature release of proinsulin-rich immature granules in both conditions. However, recent human and animal studies suggest that normal p-cells respond to an increase in synthetic demand by enhancing their ability to process proinsulin. Thus, impaired processing of proinsulin is likely in NIDDM. A new point of similarity with insulinoma has been the demonstration of a novel pancreatic peptide isolated from insulinomas and the pancreas of patients with NIDDM. This peptide, named islet amyloid polypeptide or amylin, is also present in normal islets. Because of its association with two apparently dissimilar disease states, we propose a hypothesis that encompasses the observations related to proinsulin and islet amyloid polypeptide and suggest they are manifestations of the same abnormality. In this hypothesis, we suggest that this new pancreatic peptide is a normal participant in the process of proinsulin processing and storage. We also suggest that in the presence of defective proinsulin processing and insulin release, as occurs in NIDDM, hyperglycemia stimulates amylin biosynthesis so that this peptide is deposited in increased quantities in the islet as amyloid. This then further exacerbates the diabetic process, resulting in progressive hyperglycemia and deterioration in islet function. Diabetes 38:1333-36, 1989 glycemic patients and therefore has been considered to be an end stage of the disease in which progressive hyperglycemia causes an increased stimulation to the p-cell, which responds by secreting incompletely processed granules containing proinsulin and partial cleavage products of proinsulin with reduced biological potency. Support for this idea was given by our observation several years ago that experimentally increasing insulin demand further exacerbated the proinsulin abnormality (7); that is, when hyperglycemic NIDDM patients who had a relative proinsulin excess were treated with stero~ds for 3 days to increase insulin resistance, there was a further doubling in the proportions of circulating proinsulin-to-insulin levels. However, the same steroid treatment given to weight-matched healthy control subjects also produced a similar proportionate increase in proinsulin levels. We considered both increases to be due to increased release of immature granules, rather than to a change in the clearance of insulin or proinsulin, because a similar acute increment in proinsulin was found after the administration of an arginine bolus. Thus, control and diabetic islets seemed to respond with disproportionate proinsulin release to the corticosteroid-induced increased demand for insulin secretion. This is surprising if hyperproinsulinemia is believed to be an end stage of IVIDDM. Therefore, we have explored alternative explanations. In this article, we review some recent observations and literature that have caused us to reevaluate the conclusion that increased proinsulin release in NIDDM is just due to increased demand. Instead, we suggest that hyperproinsulinemia is related to an intrinsic B-cell defect in NIDDM and that such a finding is a clue to'the etiology of the loss of B-cell secretorv ca~aci tv we have observed (8-10). a , ,