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The combined effects of menopause and dietary glucosamine on the development of insulin resistance.

G lucosamine is a naturally occurring amino-adducted sugar that serves as a precursor substrate in the glycosylation of proteins and lipids. In mammals, glucosamine is a principal precursor for the production of glycosaminoglycans, which serve as a major structural and water-retentive component of joint cartilage. Glucosamine is one of the most widely used nonvitamin or nonmineral nutritional supplements available over the counter, and it is consumed as sulfate or chondroitin derivatives. Results from countless studies have shown the utility of glucosamine in alleviating joint pain associated with osteoarthritis. However, several studies have concluded that glucosamine supplementation contributes to the development of glucose intolerance and, potentially, insulin resistance. As with glucose, glucosamine is metabolized by the hexosamine pathway, with the end product monomer UDP-N-actylglucosamine serving as the individual subunit of glycosaminoglycan chains. Some evidence exists to suggest that the hexosamine biosynthetic pathway regulates the cellular uptake of glucose. Here, excessive flow of substrate into the hexosamine pathway, whether from glucose or glucosamine or from the intracellular accumulation of glucosamine metabolites, may contribute to the development of insulin resistance. At least in skeletal muscle, acceleration of the hexosamine pathway inhibits the insulinstimulated intracellular trafficking of the glucose transporter GLUT4 from intracellular vesicles to the cell surface, and this is a hallmark feature of insulin resistance. Glucosamine has also been shown to induce hypertrophy, dysfunction, and even apoptosis of the insulin-producing A-cells of the pancreas. In isolated cultured rat islet cells, glucosamine dose dependently attenuates glucose-induced insulin release, a finding that may stem from reduced glucokinase activity. Similar results have been reported in vivo when glucosamine is infused intravenously in rats and humans. Experiments using cell culture approaches suggest that glucosamine modifies cell adhesion functions in pancreatic A-cells through modifications in the cell adhesion complex protein paxillin. Although many studies overwhelmingly suggest that glucosamine has deleterious effects on the metabolism of glucose and insulin resistance, others find no relationship between glucosamine supplementation and these metabolic irregularities. Discrepancies probably derive from differences in tissues studied, animal versus human systems, in vitro studies reliant on cell culture work versus efforts made in vivo, and the length and route of glucosamine administration. For instance, whereas in one study, short-term glucosamine did not influence insulin sensitivity in humans, another study demonstrated that long-term glucosamine treatment does attenuate insulin release. Furthermore, oral administration of glucosamine did not cause insulin resistance in lean subjects, nor did it worsen insulin resistance in obese subjects. The prevalence of being overweight and obesity increases continuously until age 80 years in women, and this correlates well with increased occurrences of metabolic syndrome, insulin resistance, and type 2 diabetes. A spike in weight gain appears after menopause when estradiol levels plummet because of ovarian failure. After menopause, a shift toward abdominal adiposity occurs, and this can be reversed through estrogen therapy. In this issue of Menopause, Kang et al use an ovariectomized rat model of menopause to assess the capacity of glucosamine to induce insulin resistance. The novelty of the Kang et al study is that it overlays the condition of menopause and subsequent increased body mass index onto the effects of glucosamine as a contributor in the development of insulin resistance. The rationale for completing this study, derived largely from animal studies, is that the loss of ovarian function is associated with the risk of developing diabetes, and estrogen supplementation has been shown to reverse this pathophysiological state. Furthermore, as outlined above, glucosamine has been shown in many studies to also facilitate the development of insulin resistance. There is strong evidence that ovarian function is a determinant in the development of insulin resistance and metabolic syndrome, both of which are contributing factors in the etiology of type 2 diabetes. Collectively, the findings of Kang et al suggest that ovarian factors such as estrogens serve a protective role in maintaining insulin sensitivity while preventing the development of metabolic syndrome and type 2 diabetes mellitus in response to glucosamine supplementation. The positive effects of estrogen in attenuating the development of insulin resistance here is supported by the fact that estrogen increases sensitivity in tissues like the liver by decreasing gluconeogenesis and glycogenolysis and by increasing pancreatic A-cell release of insulin. Estrogen also attenuates apoptosis of islet cells, reduces proinflammatory signaling via the nuclear factor-JB pathway, and enhances insulin actions in postmenopausal women More mechanistic studies are necessary to understand in greater detail how estrogens attenuate glucosamine-induced insulin resistance such as