but several investigations found no evidence that this occurs. Other studies conducted in lean or obese subjects concluded that oral glucosamine at standard doses does not affect insulin resistance. Biochemistry Glucosamine is naturally present in the shells of shellfish, animal bones, bone marrow, and fungi. D-Glucosamine is made naturally in the form of glucosamine-6-phosphate, and is the biochemical precursor of all nitrogen-containing sugars. Specifically in humans, glucosamine-6-phosphate is synthesized from fructose 6-phosphate and glutamine by glutamine—fructose-6-phosphate transaminase as the first step of the hexosamine biosynthesis pathway. The end-product of this pathway is uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), which is then used for making glycosaminoglycans, proteoglycans, and glycolipids. As the formation of glucosamine-6-phosphate is the first step for the synthesis of these products, glucosamine may be important in regulating their production; however, the way that the hexosamine biosynthesis pathway is actually regulated, and whether this could be involved in contributing to human disease remains unclear. Manufacturing Most glucosamine is manufactured by processing chitin from the shells of shellfish including shrimp, lobsters, and crabs. To meet the demands of vegetarians and others with objections to shellfish, manufacturers have brought glucosamine products to market made using fungus Aspergillus niger and from fermenting corn. History Glucosamine was first prepared in 1876 by Georg Ledderhose by the hydrolysis of chitin with concentrated hydrochloric acid. The stereochemistry was not fully determined until the 1939 work of Walter Haworth. Legal status United States In the United States, glucosamine is not approved by the Food and Drug Administration (FDA) for medical use in humans. Since glucosamine is classified as a dietary supplement in the United States, evidence of safety is required by FDA regulations, but evidence of efficacy is not required so long as it is not advertised as a treatment for a medical condition. In 2004, the FDA declared there was insufficient evidence for supplement manufacturers to state that glucosamine was effective for treating arthritis, joint degeneration, or cartilage deterioration, a position remaining in effect as of 2018. Europe In most of Europe, glucosamine is approved as a medical drug and is sold in the form of glucosamine sulfate. In this case, evidence of safety and efficacy is required for the medical use of glucosamine and several guidelines have recommended its use as an effective and safe therapy for osteoarthritis. The Task Force of the European League Against Rheumatism (EULAR) committee has granted glucosamine sulfate a level of