Measuring Insulin Resistance in Humans.

BACKGROUND: Insulin resistance is a pathophysiological condition associated with diabetes and cardiometabolic diseases that is characterized by a diminished tissue response to insulin action. Our understanding of this complex phenomenon and its role in the pathogenesis of cardiometabolic diseases is rooted in the discovery of insulin, its isolation and purification, and the challenges encountered with its therapeutic use. SUMMARY: In this historical perspective, we explore the evolution of the term "insulin resistance" and demonstrate how advances in insulin and glucose analytics contributed to the recognition and validation of this metabolic entity. We identify primary discoveries which were pivotal in expanding our knowledge of insulin resistance, the challenges in measurement and interpretation, contemporary techniques, and areas of future exploration. Key Message: Measurements of insulin resistance are important tools for defining and treating cardiometabolic diseases. Accurate quantification of this pathophysiological entity requires careful consideration of the assumptions and pitfalls of the methodological techniques and the historical and clinical context when interpreting and applying the results.

Use of fructosyl peptide oxidase for HbA1c assay.

ARKRAY, Inc developed the world's first automatic glycohemoglobin analyzer based on HPLC (1981). After that, ARKRAY developed enzymatic HbA1c assay "CinQ HbA1c" with the spread and diversification of HbA1c measurement (2007). CinQ HbA1c is the kit of Clinical Chemistry Analyzer, which uses fructosyl peptide oxidase (FPOX) for a measurement reaction. This report mainly indicates the developmental background, measurement principle, and future of the enzymatic method HbA1c reagent.

Development of NuQ nucleosome blood tests for the detection of colon cancer.

Dr Jake Micallef speaks to Hannah L Wilson, Commissioning Editor: Dr Micallef has 20 years of experience in research and development and in the management of early-stage biotechnical companies, including the manufacture of biotechnology products and the establishment of manufacturing operations. Dr Micallef gained this experience while working for WHO over a 10-year period from 1985. While working for WHO, Dr Micallef developed new diagnostic products in the areas of reproductive health and cancer. In 1990 he commenced development of a new diagnostic technology platform for WHO that was launched in 1992 and supported 13 tests. Dr Micallef also initiated and implemented in-house manufacture (previously outsourced to Abbott Diagnostics Inc., Dartford, UK) and worldwide distribution of these products for WHO. In 1990, he started a 'not-for-profit' WHO company, Immunometrics Ltd (London, UK), which marketed and distributed those diagnostic products worldwide. In 1999 Dr Micallef studied for an MBA and went on to co-found Gene Expression Technologies Ltd (London, UK) in 2001 where he successfully lead the development of the chemistry of the GeneICE technology and implemented the manufacture of GeneICE molecules. He also played a major role in business development and procured a GeneICE contract with Bayer Pharmaceuticals (Leverkusen, Germany). From 2004 to 2007, he taught 'science and enterprise' to science research workers from four universities at CASS Business School (London, UK) before joining Cronos Therapeutics (London, UK) in 2004. In 2006 Cronos was listed in the UK on AIM, becoming ValiRx. Dr Micallef continued to work as Technical Officer for ValiRx, where he in-licensed the Hypergenomics and Nucleosomics technologies and co-founded ValiBio SA (Namur, Belgium), which is now Belgian Volition SA, a subsidiary of Singapore Volition. Dr Micallef was educated at King's College London (UK; BSc, Biology and Chemistry, 1977; PhD Physical Chemistry, 1981), St Thomas' Hospital Medical School, London (UK; MSc Chemical Pathology, 1985) and Imperial College Management School (UK; MBA, 2000).

Detection of autologous blood transfusions in athletes: a historical perspective.

Autologous blood transfusions (ABTs) has been used by athletes for approximately 4 decades to enhance their performance. Although the method was prohibited by the International Olympic Committee in the mid 1980s, no direct detection method has yet been developed and implemented by the World Anti-Doping Agency (WADA). Several indirect methods have been proposed with the majority relying on changes in erythropoiesis-sensitive blood markers. Compared with the first methods developed in 1987, the sensitivity of subsequent tests has not improved the detection of blood doping. Nevertheless, the use of sophisticated statistical algorithms has assured a higher level of specificity in subsequent detection models, which is a crucial aspect of antidoping testing particularly to avoid "false positives." Today, the testing markers with the best sensitivity/specificity ratio are the Hbmr model (an algorithm based on the total amount of circulating hemoglobin level [hemoglobin level mass] and percentage of reticulocytes, 4.51·ln(Hbmass)-√%ret) and the OFF-hr model (algorithm based on hemoglobin level concentration and percentage of reticulocytes, Hb(g/L)-60·âˆš%ret). Only the OFF-hr model is currently approved by WADA. Recently, alternative indirect strategies for detecting blood doping have been proposed. One method is based upon a transfusion-induced immune-response resulting in specific changes in gene expression related to leukocytes such as T lymphocytes. Another method relies on detecting increased plasticizer metabolite levels in the urine caused by the leakage of plasticizers from the blood bags used during the blood storage. These methods need further development and validation across different types of transfusion regimes before they can be implemented. In addition, several research projects have been funded by WADA in recent years and are now under development including "Detection of Autologous Blood Transfusions Using Activated Red Blood Cells (the red blood cells eNOS system)" and "Detection of Autologous Blood Transfusion by Proteomic: Screening to find Unique Biomarkers, Detecting Blood Manipulation from Total Hemoglobin Mass using 15-nitric Oxide as a Tracer Gas, Storage Contamination as a Potential Diagnostic Test for Autologous Blood Transfusion and Test for Blood Transfusion (Autologous/Homologous) based on Changes of Erythrocyte Membrane Protome" (WADA, WADA Funded Research Projects. http://www.wada-ama.org/en/Science-Medicine/Research/Funded-Research-Projects/. 2010). Although strategies to detect autologous blood transfusion have improved, a highly sensitive test to detect small volumes of transfused autologous blood has not yet been implemented.

Essentials in the diagnosis of acid-base disorders and their high altitude application.

This report describes the historical development in the clinical application of chemical variables for the interpretation of acid-base disturbances. The pH concept was already introduced in 1909. Following World War II, disagreements concerning the definition of acids and bases occurred, and since then two strategies have been competing. Danish scientists in 1923 defined an acid as a substance able to give off a proton at a given pH, and a base as a substance that could bind a proton, whereas the North American Singer-Hasting school in 1948 defined acids as strong non-buffer anions and bases as non-buffer cations. As a consequence of this last definition, electrolyte disturbances were mixed up with real acid-base disorders and the variable, strong ion difference (SID), was introduced as a measure of non-respiratory acid-base disturbances. However, the SID concept is only an empirical approximation. In contrast, the Astrup/Siggaard-Andersen school of scientists, using computer strategies and the Acid-base Chart, has made diagnosis of acid-base disorders possible at a glance on the Chart, when the data are considered in context with the clinical development. Siggaard-Andersen introduced Base Excess (BE) or Standard Base Excess (SBE) in the extracellular fluid volume (ECF), extended to include the red cell volume (eECF), as a measure of metabolic acid-base disturbances and recently replaced it by the term Concentration of Titratable Hydrogen Ion (ctH). These two concepts (SBE and ctH) represent the same concentration difference, but with opposite signs. Three charts modified from the Siggaard-Andersen Acid-Base Chart are presented for use at low, medium and high altitudes of 2500 m, 3500 m, and 4000 m, respectively. In this context, the authors suggest the use of Titratable Hydrogen Ion concentration Difference (THID) in the extended extracellular fluid volume, finding it efficient and better than any other determination of the metabolic component in acid-base disturbances. The essential variable is the hydrogen ion.

The late Greco-Roman and Byzantine contribution towards the evolution of laboratory examinations of bodily excrement. Part 2: sputum, vomit, blood, sweat, autopsies.

Although the establishment of medical laboratory institutions was a continuous process that matured only after the 16th century, several attempts had already been made to attain a diagnosis by investigating bodily excrement. In the first part of our work, published in a previous issue of this journal, we presented data on urine, sperm, menses and stools. In this paper we present data on sputum, vomit, blood, sweat, and autopsies, thus completing the list of human materials used for laboratory examinations. All the data used are extracted from codices of Late Antiquity and Byzantium and translated by us. We did not study medical texts from the other great ancestors of Western medicine, namely Arabic and Jewish writings. From the texts cited, it is apparent that the lack of technological means was no obstacle for the doctor to create an "examinational" mind, i.e., to try to correlate the macroscopic findings in the excrement with the pathophysiological mechanism that induced them, solely with the use of the senses. This not only applies to the examination of urine, as is commonly assumed, but also to many other excrements of the upper and lower orifices of the body, as well as the human body as a whole.

Richard Havel, Howard Eder, and the evolution of lipoprotein analysis.

In 1956, the JCI published a paper by Richard Havel, Howard Eder, and Joseph Bragdon on a method using an ultracentrifuge to physically separate plasma lipoproteins and chemical methods to analyze their lipid constituents. This paper has been much cited (7081 times as of this writing) in part because it represents a solid method that, with various modifications, has been applicable for the study of lipoproteins for almost half a century.

One thing leads to another.

In 1956, the JCI published an article by Vincent Dole on a method for titrating plasma fatty acids that uncovered the importance of fatty acids as a substrate for glucose metabolism. When asked to prepare a historical perspective on this very popular paper, I paid Dole a visit and we reminisced. His answer to my question of how he came to do this work on plasma fatty acids was: "Well, one thing leads to another." Let me remind the reader of what "things" were like in 1956 and how they might have related to Dole's important contribution.

Early blood chemistry in Britain and France.

I review here key research in the early years of the field of blood chemistry. The review includes successes and limitations of animal chemistry in the critical period of the eighteenth and nineteenth centuries. Eighteenth century medical theories emphasized the primacy of body solids. Body fluids were governed by the tenets of humoral pathology. After Boerhaave sparked interest in the chemistry of the body fluids, a new humoralism developed. With the rise of animal chemistry in the eighteenth century, two complementary ideas came into play. The concept of vital force was introduced in 1774, and the chemical composition of animal matters, including the blood, began to be investigated. In the early nineteenth century, the development of new methods of analysis encouraged such chemical studies. Prominent chemists led the field, and physicians also became involved. Physiologists were often opposed to the chemical tradition, but François Magendie recognized the importance of chemistry in physiology. Liebig linked the formation and functions of the blood to general metabolism and so extended the scope of animal chemistry from 1842. About the same time, microscopic studies led to discoveries of the globular structure of the blood, and Magendie's famous pupil, Claude Bernard, began the animal chemistry studies that led him to new discoveries in hematology. This review addresses discoveries, controversies, and errors that relate to the foundations of clinical chemistry and hematology and describes contributions of instrumental investigators.