Acute Hyperglycemia Induces a Global Downregulation of Gene Expression in Adipose Tissue and Skeletal Muscle of Healthy Subjects

Abstract

To define the effects of acute hyperglycemia per se (i.e., without the confounding effect of hyperinsulinemia) in human tissues in vivo, we performed global gene expression analysis using microarrays in vastus lateralis muscle and subcutaneous abdominal adipose tissue of seven healthy men during a hyperglycemic-euinsulinemic clamp with infusion of somatostatin to inhibit endogenous insulin release. We found that doubling fasting blood glucose values while maintaining plasma insulin in the fasting range modifies the expression of 316 genes in skeletal muscle and 336 genes in adipose tissue. More than 80% of them were downregulated during the clamp, indicating a drastic effect of acute high glucose, in the absence of insulin, on mRNA levels in human fat and muscle tissues. Almost all the biological pathways were affected, suggesting a generalized effect of hyperglycemia. The induction of genes from the metallothionein family, related to detoxification and free radical scavenging, indicated that hyperglycemia-induced oxidative stress could be involved in the observed modifications. Because the duration and the concentration of the experimental hyperglycemia were close to what is observed during a postprandial glucose excursion in diabetic patients, these data suggest that modifications of gene expression could be an additional effect of glucose toxicity in vivo. Diabetes 56:992-999, 2007 A ltered glycemic control in individuals with type 1 and type 2 diabetes is associated with increased risk of micro-and macrovascular complications (1). The mechanisms of the deleterious effects of hyperglycemia, which is referred to as glucotoxicity, have been largely investigated. It is accepted that oxidative stress induced by hyperglycemia could be the main cause of the different pathways leading to diabetes complications (2,3). Importantly, acute glucose fluctuations exhibit a more specific triggering effect on oxidative stress than chronic sustained hyperglycemia (4). Furthermore, acute hyperglycemia induces deleterious effects in various tissues and, from epidemiological studies, the harmful effect of hyperglycemia for cardiovascular complications appears to be mainly related to postprandial glucose excursion (5).On the other hand, excess carbohydrate leads to the activation of several genes that promote storage of glycogen and triglycerides in liver, skeletal muscle, and adipose tissue (6). Although these effects are generally produced through a combined action with insulin, the identification of a glucose-responsive transcription factor named ChREBP (carbohydrate responsive element binding protein) (7,8) has recently shed new light on the mechanisms whereby glucose could directly affect gene transcription.Until now, the effects of high glucose concentrations have mostly been studied in cell culture experiments and using animal models, and little is known about the in vivo molecular mechanisms of hyperglycemia in human tissues. The development of microarray technology offers powerful tools for characterizing the consequence...

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