[Show abstract][Hide abstract] ABSTRACT: At the cellular level, the three hormone-related ligands - IGF-2, IGF-1, and insulin - all bind to four (or more) types of IGF-1 receptors and insulin receptors (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-2 receptor (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.Origins: From 1910-1930, 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 insulin-like growth factors, their binding proteins and assays to measure them; receptors for the insulin-related peptides, as well as the intracellular pathways beyond the receptor.In closing, we replace non-islet cell tumor hypoglycemia (NICTH), an outdated and misleading label, with IGF-2-oma, self-explanatory and consistent with names of other hormone-secreting tumors.
[Show abstract][Hide abstract] ABSTRACT: This edition of 'Then and now' re-examines Lise Heding's very highly cited paper 'Radioimmunological determination of human C-peptide in serum', which was published in Diabetologia in 1975. We show how this article and other related articles by Heding contributed to heightened respect for C-peptide (and transformation of Heding's research programme). Initially thought of as an inert discard, C-peptide in blood is now recognised as an excellent surrogate measure of insulin secretion under a wide range of conditions. The assay is especially valuable for acute ascertainment of the insulin secretory capabilities of patients with type 1 diabetes or of transplanted beta cells. The assay is also being used to monitor endogenous beta cell loss or in vivo expansion of beta cell mass over the long term. We conclude with two promising future applications: (1) measurements of C-peptide in blood (along with insulin, glucose, and HbA(1c)) at annual intervals as a potential approach to earlier diagnosis of diabetes; and (2) among many recent advances in recognising properties of C-peptide (including status as a candidate hormone), most promising is C-peptide as a possible therapy for diabetic neuropathy and nephropathy.
[Show abstract][Hide abstract] ABSTRACT: In the symposium entitled "Transcriptional controls of energy sensing," the authors presented recent advances on 1) AMP kinase, an intracellular energy sensor; 2) PGC-1α (peroxisome proliferator-activated receptor γ co-activator 1α), a transcriptional co-activator that has powerful effects on mitochondria; 3) methylation and demethylation in response to metabolic fluctuations; and 4) FGF21 (fibroblast growth factor 21) as an emerging hormone-like intercellular metabolic coordinator. This introduction places these advances within a broad overview of energy sensing and energy balance, with a focus on human evolution and disease. Four key elements of human biology are analyzed: 1) elevated body temperature; 2) complex prolonged reproductive pathways; 3) emergence of 4 large, well-defined fat depots, each with its own functional role; and 4) an immune system that is often up-regulated by nutrition-related signals, independent of the actual presence of a pathogen. We propose that an overactive immune system, including the "metabolic syndrome," was adopted evolutionarily in the distant past to help hold out against unconquerable infections such as tuberculosis, malaria, and trypanosomiasis. This immune activation is advantageous in the absence of other disease management methods, especially under conditions in which life expectancy is short. The inflammation has become a major agent of pathology in wealthy populations in whom the pathogens are a minor threat and life expectancy is long. The "Conclusions" section sketches cautiously how understanding the molecules involved in energy sensing and energy balance may lead to specific therapies for obesity and diabetes and for their complications.
American Journal of Clinical Nutrition 02/2011; 93(4):875S-83. DOI:10.3945/ajcn.110.001909 · 6.77 Impact Factor