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ZACHARY T. BLOOMGARDEN O N - Hyperinsulinemia and insulin secretion abnormalities Hyperinsulinemia causing IR. Jesse Roth (New York, NY) suggested that, rather than IR, hyperinsulinemia should be considered the major mediator of adverse outcome, with hyperinsulinemia the underlying characteristic of all syndromes of IR (1). Recalling Edgar Allan Poes story The Purloined Letter, Roth argued that the mediator of IR is insulin, which is hidden in plain sight, causing hormone-induced inhibition of hormone action. Similar phenomena are seen in choriocarcinoma, in which enormous amounts of human chorionic gonadotropin have no biological effect, in the divergence between the effect of gonadotropinreleasing hormone, which enhances fertility when given in a pulsatile fashion, while when administered continuously, it halts precocious puberty, or between the effect of parathormone given continuously, causing bone resorption, while bolus administration increases bone formation. High levels of insulin similarly decrease the effectiveness of insulin, and mice overexpressing the insulin gene, with doubling and quadrupling insulin levels, fail to show change in weight or fasting glucose, while developing IR, postprandial hyperglycemia, and decreased insulin receptor binding. Similar effects of hyperinsulinemia may be demonstrated in normal rats that are given increasing daily doses of insulin or that have hypothalamic damage, whereas ob/ob mice that are given alloxan or streptozotocin show improvement in insulin sensitivity. In humans, the Somogyi effect is of decreasing insulin doses improving glycemia, whereas patients with insulinoma develop IR, and pulsatile administration in a manner mimicking its physiologic release appears to have greater biologic effect than that of continuous infusion of a considerably greater amount of insulin (2). Basal insulin levels are twice as great in type 2 diabetic as in normal persons, despite fairly marked fasting hyperglycemia, so that although postload insulin levels are decreased, Roth argued that IR, rather than deficiency, mediates the hyperglycemia of type 2 diabetes, with IR potentially mediating defects in insulin secretion, as insulin receptor activation appears to be required for -cell glucose recognition. Presumably, Roth argued, other insulin responsive tissues such as the brain and the macrophage also develop IR as a function of hyperinsulinemia, leading to unbalanced effects from one tissue to the next. A wide variety of treatments including exercise, diet, m e t f o r m i n , a c a r b o s e , a n d t h i a z o lidinediones reduce basal insulin levels and are associated with improvement in metabolic profile, whereas, at 20-year follow-up, basal hyperinsulinemia is the best predictor of subsequent diabetes (3), taking into account measures of obesity and glycemia. Diabetes is not a simple disease, and its complications are complex, but while microvascular disease is de monstrably related to glucose concentrations, Roth termed the link of glycemia to macrovascular disease difficult to demonstrate and really marginal, so that earlier treatment initiation may delay the disease process. Furthermore, given the rather rapid shift that occurs from normal to high levels of glucose (and insulin), Roth suggested that the rapidity of change in these measures be taken into account in determining which patients with early disease require treatment and argued somewhat against the use of insulin in early diabetes treatment, endeavoring instead to get at this much earlier to reduce adverse outcome. Insulin secretory dysfunction and IR Kristina Utzschneider (Seattle, WA) discussed the role of -cell dysfunction in glucose metabolism, pointing out that in type 2 diabetes IR is accompanied by -cell dysfunction with -cell apoptosis and subsequent loss of compensation (4). It has long been recognized that -cell mass is decreased in type 2 diabetes (5), while obesity increases -cell volume (6). Both impaired fasting glucose and type 2 diabetes are associated with normal -cell replication rates but increased a

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