Adipose-specific overexpression of GLUT4 reverses insulin resistance and diabetes in mice lacking GLUT4 selectively in muscle

Abstract

Adipose tissue plays an important role in glucose homeostasis and affects insulin sensitivity in other tissues. In obesity and type 2 diabetes, glucose transporter 4 (GLUT4) is downregulated in adipose tissue, and glucose transport is also impaired in muscle. To determine whether overexpression of GLUT4 selectively in adipose tissue could prevent insulin resistance when glucose transport is impaired in muscle, we bred muscle GLUT4 knockout (MG4KO) mice to mice overexpressing GLUT4 in adipose tissue (AG4Tg). Overexpression of GLUT4 in fat not only normalized the fasting hyperglycemia and glucose intolerance in MG4KO mice, but it reduced these parameters to below normal levels. Glucose infusion rate during a euglycemic clamp study was reduced 46% in MG4KO compared with controls and was restored to control levels in AG4Tg-MG4KO. Similarly, insulin action to suppress hepatic glucose production was impaired in MG4KO mice and was restored to control levels in AG4Tg-MG4KO. 2-deoxyglucose uptake during the clamp was increased approximately twofold in white adipose tissue but remained reduced in skeletal muscle of AG4Tg-MG4KO mice. AG4Tg and AG4Tg-MG4KO mice have a slight increase in fat mass, a twofold elevation in serum free fatty acids, an approximately 50% increase in serum leptin, and a 50% decrease in serum adiponectin. In MG4KO mice, serum resistin is increased 34% and GLUT4 overexpression in fat reverses this. Overexpression of GLUT4 in fat also reverses the enhanced clearance of an oral lipid load in MG4KO mice. Thus overexpression of GLUT4 in fat reverses whole body insulin resistance in MG4KO mice without restoring glucose transport in muscle. This effect occurs even though AG4Tg-MG4KO mice have increased fat mass and low adiponectin and is associated with normalization of elevated resistin levels.

RETRACTED ARTICLE:l-glutamine supplementation induces insulin resistance in adipose tissue and improves insulin signalling in liver and muscle of rats with diet-induced obesity

“…In addition, in adipose-specific GLUT4 knockout mice insulin resistance is likely to be caused by increased expression and secretion of retinol binding protein 4 (RBP4) from adipose tissue [39]. On the other hand, GLUT4 overexpression in adipose tissue could protect against insulin resistance [40,41]. In this regard, it should be mentioned that modulation of the expression and secretion of RBP4 by adipose tissue may have an important role in whole-body insulin sensitivity, as previously demonstrated in other animal models and in humans [39,42].…”

Regulation of glucose transporter type 4 isoform gene expression in muscle and adipocytes

“…Indeed, studies from human type 2 diabetes (T2DM) or animal models (ob/ob and db/db mice) suggest that GLUT4 gene expression is controlled at the transcriptional level. Tissue-specific knockout of the GLUT4 gene resulted in insulin resistance (9), while overexpression of GLUT4 resulted in the restoration of whole body glucose disposal and insulin sensitivity (10). Because skeletal muscle is the major tissue for glucose disposal, most studies regarding gene expression have been performed in this tissue.…”

“…Moreover, adipose tissue-specific GLUT4 knockout mice revealed decreased glucose tolerance and insulin sensitivity (12), while overexpression improved insulin resistance (10). These results imply that adipose tissue-specific GLUT4 gene expression also plays a pivotal role in glucose homeostasis (10). Thus, understanding the regulation mechanism of GLUT4 gene expression both in muscle and adipose tissue may provide valuable information in the development of anti-obesity or antidiabetes drugs.…”

Diabetes Mellitus as Dysfunction of Interactions among all Organs: “Ominous Orchestra of Organs”

“…Conversely, some "adipo(cyto)kines", secreted from adipocytes, are involved in hepatic insulin resistance [10]. Furthermore, adipose-specifi c overexpression of GLUT4 reverses insulin resistance and diabetes in mice lacking GLUT4 selectively in muscle [25]. This result could not be explained by known adipokines, such as adiponectin, or resistin.…”