Another link between exercise and relief from postmenopausal decline
Derivatized forms of glucosamine also play essential metabolic functions within most eukaryotic cells. For example, N-acetylglucosamine becomes posttranslationally O-linked to serine and threonine amino acid residues of intracellular proteins. Similar to protein phosphorylation, O-linked β-N-acetylglucosamination modifies protein activity, the ability to interact with other intracellular proteins, and degradation. Dysregulated O-linked β-N-acetylglucosamination is thought to be responsible for a number of human pathologies including cardiovascular disease, cancer, diabetes, and neurodegenerative diseases.9-11 O-linked β-N-acetylglucosamination plays an essential role in regulating microtubule-associated protein tau, the protein most commonly associated with Alzheimer's disease.12 More recently, O-linked β-N-acetylglucosamination has been shown to regulate gene transcription through epigenetic regulation of chromatin structure and assembly of protein transcriptional complexes.13 It is becoming increasingly clear that disruption of homeostatic glucosamine levels results in the development of disease states. The exact mechanism by which glucosamine contributes to these diseases is not clear, but it is likely related to forced acceleration of the hexosamine pathway. Here, excess glucosamine funneled into this pathway results in elevated production of N-acetylglucosamine, which in turn results in aberrant O-linked β-N-acetylglucosamination of proteins within any given cell. This alters protein function, half-life, and cellular localization. Not surprisingly, there is a strong relationship between insulin resistance and excessive O-linked β-N-acetylglucosamination of specific components of insulin signaling.14 The resultant faulty insulin signaling is a precursor to many of the aforementioned diseases.
Postmenopausal women are at increased risk of developing type 2 diabetes and insulin resistance stemming in part from a spike in weight gain that is accompanied by a shift toward abdominal adipose deposition. Laboratory studies in recent years by Kang et al15,16 have used the ovariectomized rat model of menopause to evaluate the impact of glucosamine supplementation on insulin resistance. In their initial investigation, they reported that ovariectomized rats treated with glucosamine appear with elevated plasma glucose, and also elevated fasting plasma insulin and higher homeostatic model assessment of insulin resistance (HOMA-IR). Furthermore, plasma insulin, plasma glucose, and HOMA-IR were all shown to increase upon intraperitoneal injection of glucose, but only in ovariectomized rats treated with glucosamine. Furthermore, glucosamine caused a decrease in the expression of skeletal muscle GLUT-4 and an increase in pancreatic islet hyperplasia in ovariectomized rats.15 This was then followed by a second study showing that in ovariectomized rats, glucosamine caused a decrease in the expression of insulin while inducing apoptosis of pancreatic β-cells. It was also established that glucosamine disrupted calcium signaling in cultured β-cells, which blocked insulin secretion.