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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #149: Glucose Toxicity Part 5

Oct 30, 2018

O-GlcNAc signaling as an adaptive response to overnutrition

The effects are consistent with a role for O-GlcNAc in damping acute hormone- and phosphorylation-mediated signals in situations of chronic nutrient excess. Although discovered in the context of diabetes, the aforementioned changes mediated by the HBP can also be viewed as adaptive responses to excess nutrient flux: muscle cells protect themselves from excess glucose fluxes and the excess nutrients are eventually stored as fat. Indeed, if insulin signaling were not dampened and glycogen synthesis were effectively engaged even with overeating, a pound of ingested carbohydrate would result in approximately four pounds of hydrated glycogen in muscle, and it is easy to visualize diets rich in sodas and donuts resulting in the development of glycogen storage diseases. With age and chronic overstimulation of the pathway, however, animals with chronically increased hexosamine flux exhibit several of the maladaptive features of the type 2 diabetes syndrome including obesity, hyperlipidemia, insulin resistance, and β-cell failure [44,47,80].Thus, the HBP can be viewed as both physiologic and pathophysiologic, triggering normal nutrient regulation as well as aspects of “glucose toxicity” and the metabolic syndrome.

O-GlcNAc and other aspects of glucose toxicity

The O-GlcNAc pathway also plays a role in hepatic glucose production and insulin secretion, the other key abnormalities of type 2 diabetes.The glycosylation of FOXO1, a key regulator of gluconeogenesis, was mentioned earlier. This glycosylation is mediated, at least in part, through the binding of OGT to O-GlcNAc-modified PGC1α, resulting in the targeting of OGT to binding partners of PGC1α that include the FOXOs [59]. It was also demonstrated that overexpression of O-GlcNAcase in the liver of insulin resistant db/db mice significantly improved glucose and insulin tolerance [81]. This was mediated by decreased O-glycosylation of the cyclic adenosine monophosphate response element-binding protein 2 (CRTC2), which led to decreased expression of gluconeogenic enzymes.

Transcriptional regulation by O-GlcNAc has been shown to play a major role in the pancreatic β cell, where OGT is highly expressed [82]. GFA overexpression targeted to the β cell resulted in early hyperinsulinemia but eventual β-cell failure as the transgenic mice age [47]. Conversely, O-GlcNAcase overexpression led to early insulin deficiency but long-term protection from age- and obesity-related β-cell failure [83]. In β cells, the best established mechanisms for the effects of O-GlcNAc signaling are transcriptional. Transcription of the insulin gene is regulated by the binding of several transcription factors including Pdx-1, NeuroD1, andMafA, all three of which are directly or indirectly regulated by O-GlcNAc (reviewed in [84]). In these examples, O-GlcNAc serves a function that stimulates insulin secretion, which would be predicted to be antidiabetic and “antiglucotoxic,” but as pointed out when these acute effects are translated into chronic models, they become prodiabetic through unclear mechanisms [47]. Insulin-independent downstream effects of O-GlcNAc, for example on inflammatory [85] or angiogenic [86] pathways, may also be at play.

Oxidative stress from excess glucose metabolism

Another major fate of glucose that has been linked to glucose toxicity is the oxidative stress that results from oxidation of abnormally heavy glucose loads. As was the case for the term “glucose toxicity,” the use of the words “oxidative stress” may connote a purely deleterious effect such as the accumulation of oxidized and dysfunctional lipids, proteins, and nucleic acids because of excess free radicals and other oxidants (e.g. peroxide, peroxynitrite, and nitric oxide), and that is certainly part of the mechanism. It is also clear, however, that the cellular redox state is equally important to the physiologic regulation of metabolism through multiple mechanisms including altering the ratios of reduced to oxidized glutathione, redox status of thiols in proteins such as thioredoxin, activity of key phosphatases, other redox-dependent posttranslational modifications such as protein nitrosylation, levels and activities of adipokines, and others. The reader is directed to recent reviews in this area for further details (e.g. [87–89]). Although the most obvious source for these reactive species is oxidative phosphorylation, other sources that are particularly relevant to diabetes and glucose toxicity include reactive products of advanced glycation end-products and glyceraldehyde autoxidation (reviewed in [90]).

Oxidative stress and ?-cell failure in diabetes

Increasing evidence links oxidative stress provoked by hyperglycemia to β-cell damage [91,92]. Interestingly, the latter reference links hexosamine signaling to induction of oxidative stress, providing one potential link between these important processes in glucose toxicity. β-Cells are particularly susceptible to oxidative stress because they contain intrinsically low concentrations of antioxidant enzymes [93]. In addition, β cells are programmed to target most of their glucose to oxidative phosphorylation for signaling of insulin secretion, so that in states of hyperglycemia there will be an added stress of increased production of oxidant species on top of the decreased ability to reduce those species. Additivity of oxidant stress with high concentrations of glucose has been directly demonstrated [94]. These findings have led to multiple studies that demonstrate that transgenic overexpression of antioxidant enzymes (both cytosolic and mitochondrial superoxide dismutase, catalase, and glutathione peroxidase) all protect from β-cell failure in isolated islets, cultured insulin-producing cells, and rodent models [95,96]. As would be predicted from these data, insulin secretory defects and the changes in genes controlling insulin secretion in several experimental models of glucose toxicity have also been prevented by various antioxidant treatments such as N-acetylcysteine, troglitazone, and aminoguanidine [91,97].

Cellular mechanisms for effects of hyperglycemia on insulin secretion

Exposure of the β cell to experimental chronic hyperglycemia induces specific desensitization to glucose whereas the insulin response to other secretagogues such as arginine [37], leucineno break [98], and isoproterenol [99] are either preserved or exaggerated. In keeping with this, the insulin content of the islet is not reduced by hyperglycemia to an extent that would account for the degree of glucose-induced desensitization [37]. Such selective desensitization to glucose but not other secretagogues such as arginine is also seen during the early types 1 and 2 diabetes.This desensitization is considered entirely reversible by restoration of normal glucose concentrations [100]. Consistent with these observations, one mechanism by which antioxidants restore normal insulin secretion is direct preservation of mitochondrial function and stimulus-secretion coupling [101]. Insulin content also is diminished by hyperglycemia: in animals and cell lines, hyperglycemia induces a gradual loss of insulin gene expression and gene and protein expression levels of pancreas duodenum homeobox-1 (PDX-1) and MafA transcription factors, critical regulators of the insulin gene, and these effects are also reversed with antioxidant treatment [91].

Oxidative stress and insulin resistance

The association of oxidant stress with insulin resistance has been documented in humans for almost two decades [102]. These effects are mirrored in cell culture models, wherein it has also been shown that antioxidants such as α-lipoic acid protects against the effects of oxidant stress on insulin signaling pathways in cultured adipocytes and myocytes [103]. These studies have prompted trials of antioxidants in humans, wherein short-term improvements in insulin sensitivity are seen [104], although the long-term benefits of antioxidant therapies in type 2 diabetes have been less encouraging. Part of the reason for the latter is likely due to the complexity of oxidant stress on insulin signaling and the function of insulin-responsive tissues. Oxidant stress in diabetes is not only linked to excess glucose and lipid fluxes, but also to ancillary factors such as tissue iron levels [105]. The targets of oxidant stress include mitochondrial respiration rates [106], the proximal insulin-signaling pathway and downstream associated pathways such as p38/MAP kinase and Jnk which are linked to inflammatory signaling [90,107], the AMP-activated protein kinase pathway [108], and numerous others, not to mention more nonspecific effects caused by the nonspecific oxidative damage to DNA, lipids, and proteins. Hence, delivery of the right species of antioxidant to the right tissues at sufficiently sustained levels will be a daunting task.