Tumors of mesenchymal and epithelial origin produce IGF-2, which activates pathways in the tumors. In a minority of patients, the tumors (hepatomas, fibromas, and fibrosarcomas are the most common among many) release into the circulation enough IGF-2-related peptides to mimic the fasting hypoglycemia characteristic of patients with insulin-producing islet-cell tumors. Rarely, markedly elevated IGF-2 levels produce somatic changes suggestive of acromegaly. Typically, the elevated IGF-2 levels are associated with suppressed plasma levels of insulin, IGF-1, and GH. Complicating the pathophysiology are the IGF binding proteins (IGFBPs) that can bind IGF-2 and IGF-1, modifying hormone metabolism and action. IGFBP concentrations are often altered in the presence of these tumors. At the cellular level, the 3 hormone-related ligands, IGF-2, IGF-1, and insulin, all bind to 4 (or more) types of IGF-1 receptor (IGF-1R) and insulin receptor (IR). Each receptor has its own characteristic affinity for each ligand, a tyrosine kinase, and overlapping profiles of action in the target cells. The IGF-2R, in addition to binding mannose-6-phosphate-containing proteins, provides an IGF-2 degradation pathway. Recent evidence suggests IGF-2R involvement also in signal transduction. Surgery, the treatment of choice, can produce a cure. For patients not cured by surgery, multiple therapies exist, for the tumor and for hypoglycemia. Potential future therapeutic approaches are sketched. From 1910 to 1930, hypoglycemia, insulin, insulinomas, and non-islet-cell tumors were recognized. The latter third of the century witnessed the emergence of the immunoassay for insulin; the IGFs, their binding proteins, and assays to measure them; and receptors for the insulin-related peptides as well as the intracellular pathways beyond the receptor. In closing, we replace non-islet-cell tumor hypoglycemia, an outdated and misleading label, with IGF-2-oma, self-explanatory and consistent with names of other hormone-secreting tumors.

Summary2012 marks the 90th year since the purification of insulin and the miraculous rescue from death of youngsters with type 1 diabetes. In this review, we highlight several previously unappreciated or unknown events surrounding the discovery. (i) We remind readers of the essential contributions of each of the four discoverers -Banting, Macleod, Collip, and Best. (ii) Banting and Best (each with his own inner circle) worked not only to accrue credit for himself but also to minimize credit to the other discoverers. (iii) Banting at the time of the insulin research was very likely suffering from post-traumatic stress disorder (PTSD) that originated during his heroic service as a surgeon in World War I on the Western Front in 1918, including an infected shrapnel wound that threatened amputation of his arm. His war record along with the newly discovered evidence of a suicide threat goes along with his paranoia, combativeness, alcohol excess, and depression, symptoms we associate with PTSD. (iv) Banting's eureka idea, ligation of the pancreatic duct to preserve the islets, while it energized the early research, was unnecessary and was bypassed early. (v) Post discovery, Macleod uncovered many features of insulin action that he summarized in his 1925 Nobel Lecture. Macleod closed by raising the question -what is the mechanism of insulin action in the body? -a challenge that attracted many talented investigators but remained unanswered until the latter third of the 20th century.

In October 2011, the University of Toronto and the TorontoheadquarteredGairdner Foundation partnered to celebrate theninetieth anniversary of the discovery of insulin. In 1921, fourscientists worked to discover, isolate, and purify insulin at theUniversity of Toronto: Frederick Banting, John J. R. Macleod,James B. Collip, and Charles H. Best. The credit for this achievementhas been assigned in varying ways. Popular opinion, inToronto and worldwide, has bestowed the recognition for discoveryupon Banting and Best. Indeed, many noted diabetologistshave credited the achievement to this pair. However, theNobel Committee awarded the Prize in Physiology or Medicineto Banting and Macleod in 1923. Michael Bliss, in his 1982history of the discovery of insulin, revisited the question ofwho really is responsible for this wonder drug. Our essay willexplore the pathway toward the discovery of insulin and seekto understand why the credit for this monumental achievementwas apportioned in such different ways.

HbA(1c) testing has become an accepted means of diagnosing diabetes as an alternative to blood glucose levels. However, population-based norms of glucose and of HbA(1c) levels do not enable the detection of diabetes at an early enough stage to thwart complications. Personal trajectories of glucose levels show steep increases a number of years prior to diabetes diagnosis. Here, we hypothesize that a comparable time-dependent deviation in an individual's HbA(1c) level may be an early manifestation of disease that should prompt lifestyle modifications. We predict that analysis of personal trajectories of glucose and of HbA(1c) will promote earlier intervention and a greater reduction in disease complications than current standards, which are based on population-based norms.