Earl Sutherland (1915-1974) [corrected] and the discovery of cyclic AMP.

In 1945, Earl Sutherland (1915-1974) [corrected] and associates began studies of the mechanism of hormone-induced glycogen breakdown in the liver. In 1956, their efforts culminated in the identification of cyclic AMP, an ancient molecule generated in many cell types in response to hormonal and other extracellular signals. Cyclic AMP, the original "second messenger," transmits such signals through pathways that regulate a diversity of cellular functions and capabilities: metabolic processes such as lipolysis and glycogenolysis; hormone secretion; the permeability of ion channels; gene expression; cell proliferation and survival. Indeed, it can be argued that the discovery of cyclic AMP initiated the study of intracellular signaling pathways, a major focus of contemporary biomedical inquiry. This review presents relevant details of Sutherland's career; summarizes key contributions of his mentors, Carl and Gerti Cori, to the knowledge of glycogen metabolism (contributions that were the foundation for his own research); describes the experiments that led to his identification, isolation, and characterization of cyclic AMP; assesses the significance of his work; and considers some aspects of the impact of cyclic nucleotide research on clinical medicine.

Seasonal regulation of the growth hormone-insulin-like growth factor-I axis in the American black bear (Ursus americanus).

The American black bear maintains lean body mass for months without food during winter denning. We asked whether changes in the growth hormone/insulin-like growth factor-I (GH-IGF-I) axis may contribute to this remarkable adaptation to starvation. Serum IGF-I levels were measured by radioimmunoassay, and IGF-binding proteins (IGFBPs) were analyzed by ligand blotting. Initial studies in bears living in the wild showed that IGF-I levels are highest in summer and lowest in early winter denning. Detailed studies in captive bears showed that IGF-I levels decline in autumn when bears are hyperphagic, continue to decline in early denning, and later rise above predenning levels despite continued starvation in the den. IGFBP-2 increased and IGFBP-3 decreased in early denning, and these changes were also reversed in later denning. Treatment with GH (0.1 mg·kg(-1)·day(-1) × 6 days) during early denning increased serum levels of IGF-I and IGFBP-3 and lowered levels of IGFBP-2, indicating that denning bears remain responsive to GH. GH treatment lowered blood urea nitrogen levels, reflecting effects on protein metabolism. GH also accelerated weight loss and markedly increased serum levels of free fatty acids and ß-hydroxybutyrate, resulting in a ketoacidosis (bicarbonate decreased to 15 meq/l), which was reversed when GH was withdrawn. These results demonstrate seasonal regulation of GH/IGF-I axis activity in black bears. Diminished GH activity may promote fat storage in autumn in preparation for denning and prevent excessive mobilization and premature exhaustion of fat stores in early denning, whereas restoration of GH/IGF activity in later denning may prepare the bear for normal activity outside the den.

From insulin and insulin-like activity to the insulin superfamily of growth-promoting peptides: a 20th-century odyssey.

In 1941, Gellhorn reported that administration of human blood to hypophysectomized/adrenodemedullated rats caused a fall in blood sugar. This was among the early demonstrations that human blood possesses glucose-lowering or insulin-like activity (ILA). Gellhorn assumed he had detected only insulin. During the 1960s, however, it became evident that plasma ILA contained at least two components: one, suppressible ILA (SILA), was inactivated by anti-insulin antibody and was therefore considered to be indistinguishable from pancreatic insulin; the other, nonsuppressible ILA (NSILA), was unaffected by anti-insulin antibody. Subsequent work resolved NSILA into insulin-like growth factors I and II (IGF-I and IGF-II), two 7.5 kilodalton peptides with potent mitogenic properties; established their identity with the somatomedins; and investigated both their therapeutic potential and role in the pathogenesis of neoplastic and other human diseases. Insulin and the IGFs exhibit striking homologies in amino acid composition and some degree of overlap in their signaling pathways and actions. Moreover, insulin-like proteins have been identified not only in all vertebrate classes but also in molluscs, insects, and worms. These observations are the basis for the hypothesis that the genes encoding vertebrate insulins and IGFs and invertebrate insulin-like molecules evolved from a common ancestral gene, and for the concept of an insulin superfamily of growth-promoting peptides.

The insulin immunoassay after 50 years: a reassessment.

In 1960 Berson and Yalow published a method for the radioimmunoassay (RIA) of plasma insulin based on the concept that the extent to which unlabeled insulin displaces labeled insulin from anti-insulin antibody is proportional to the concentration of unlabeled insulin. The RIA for insulin has greatly increased knowledge of the physiology of glucose homeostasis and of the diverse causes of diabetes mellitus. Beyond this, the insight on which the RIA-or, more broadly, the competitive protein-binding assay-is based has provided the means to measure nanomolar or picomolar concentrations of a vast array of compounds in plasma and tissues. Directly or indirectly, the RIA has profoundly affected every branch of medicine. This essay reviews the ideas that were current in the medical research community when Berson and Yalow began their work and the observations and reasoning process that led them to their seminal discovery.

Spur cell anemia in alcoholic cirrhosis: cure by orthotopic liver transplantation and recurrence after liver graft failure.

Spur cell anemia is an acquired form of hemolytic anemia caused by a structural abnormality of red cell membranes that results in spiculated erythrocytes. These peculiarly shaped red blood cells, called acanthocytes, have a shortened survival and undergo splenic sequestration and destruction. Spur cell anemia has been known to occur in several conditions, including chronic liver disease, and more specifically in alcoholic cirrhosis. Treatment of this disorder has been disappointing and usually indicates end-stage liver disease. Liver transplantation has been reported as the most effective treatment. We herein present a case of severe spur cell hemolytic anemia that successfully reverted after orthotopic liver transplantation and recurred secondary to resumption of alcohol intake and consequent liver graft failure. This case conclusively demonstrates the association among alcoholic cirrhosis, end-stage liver disease, and spur cell hemolytic anemia.