December - 20189THE THREE MECHANISMS OF GLUCOSE TOXICITYthe function of several classes of transcription factors (4). These mice are severely insulin resistant, due to defects in insulin action, particularly IRS-1/IRS-2­dependent activation of PI 3-kinase, in muscle and liver (5). Interestingly, these abnormalities were associated with a twofold increase in muscle and liver triglyceride content, and upon transplantation of fat tissue into these mice, triglyceride content in muscle and liver returned to normal, as did insulin signaling and action. These findings are consistent with the hypothesis that insulin resistance develops in obesity, type 2 diabetes, and lipodystrophy because of alterations in the partitioning of fat between the adipocyte and muscle or liver. This change leads to the intracellular accumulation of triglycerides, and, probably more importantly, of intracellular fatty acid metabolites (fatty acyl CoA's, diacylglycerol, and ceramides, among others) in these insulin-responsive tissues, which leads to acquired insulin signaling defects and insulin resistance. This hypothesis might also explain how thiazolidinediones improve insulin sensitivity in muscle and liver tissue. By activating PPAR- receptors in adipocytes and promoting adipocyte differentiation, these agents might promote a redistribution of fat from liver and muscle into the adipocytes, much as fat transplantation does in fat-deficient mice (6). This hypothesis is supported by some recent thiazolidinedione studies in rats fed high-fat diets (5, 7). It might also be expected that any alteration in the ability of muscle and liver to metabolize fatty acids, such as inherited or acquired defects in mitochondria function, would also lead to intracellular accumulation of fatty acid metabolites and subsequent defects in insulin signaling and action. Given the polygenic nature of type 2 diabetes, it is likely that examples of both of these possibilities will be identified. This mechanism, if it proves to be correct, offers many new therapeutic targets for novel insulin-sensitizing agents.An alternative hypothesis is presented herein. This hypothesis holds that the insulin receptors on cells become glycated by reacting with glucose. These glycated receptors have been altered in their structure and therefore their function is also altered. High glucose blood levels would lead to an increase in this glycation resulting in an enhanced worsening of insulin function and an increase in insulin resistance.Protein GlycationInsulin resistance is toxic due to its reactivity. Glucose is an aldehyde which reacts with the amino groups found on the amino acids of all proteins. When glucose reacts with these amino groups it forms a fructosamine bond. These glycated proteins progress through a series of reactions to become Advanced Glycation Endproducts (AGEs) (8). AGEs are believed to be responsible for many, if not all, of the disease complications associated with diabetes such as retinopathy, nephropathy and neuropathy leading to blindness, kidney failure, and amputations (9). If protein glycation could be slowed or halted, the complications of diabetes may be reduced or stopped and the progression of prediabetes to Type 2 diabetes might also be slowed or halted.An interesting approach to inhibiting protein glycation has been described using a nutritional supplement, tradenamed Lysulin, containing lysine, zinc and vitamin C (10). Double blind placebo controlled studies have shown that this supplement can lower HbA1c in as little as two weeks (11).SummaryGlucose is necessary to live, but uncontrolled or poorly controlled levels in the bloodstream are toxic. The toxicity stems from three mechanisms: insulin depletion, insulin resistance, and protein glycation. New treatments are being developed to combat these mechanisms of glucose toxicity.
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