Transgenic mice expressing the human GLUT4/muscle-fat facilitative glucose transporter protein exhibit efficient glycemic control.

Abstract

To examine the physiological role of the GLUT4/muscle-fat specific facilitative glucose transporter in regulating glucose homeostasis, we have generated transgenic mice expressing high levels of this protein in an appropriate tissue-specific manner. Examination of two independent founder lines demonstrated that high-level expression of GLUT4 protein resulted in a marked reduction of fasting glucose levels (=70 mg/dl) compared to wild-type mice ("'130 mg/dl). Surprisingly, 30 min following an oral glucose challenge the GLUT4 transgenic mice had only a slight elevation in plasma glucose levels (Q"90 mg/dl), whereas wild-type mice displayed a typical 2-to 3-fold increase (==250-300 mg/dl). In parallel to the changes in plasma glucose, insulin levels were --2-fold lower in the transgenic mice compared to the wild-type mice. Furthermore, isolated adipocytes from the GLUT4 transgenic mice had increased basal glucose uptake and subcellular fractionation indicated elevated levels of cell surface-associated GLUT4 protein. Consistent with these results, in situ immunocytochemical localization of GLUT4 protein in adipocytes and cardiac myocytes indicated a marked increase in plasma membrane-associated GLUT4 protein in the basal state. Taken together these data demonstrate that increased expression of the human GLUT4 gene in vivo results in a constitutively high level of cell surface GLUT4 protein expression and more efficient metabolic control over fluctuations in plasma glucose concentrations.The GLUT4/muscle-fat glucose transporter is one member of the facilitative glucose transporter super-gene family that is specifically expressed in muscle and adipose tissues (1, 2). In contrast to the other glucose transporter isoforms, GLUT4 contains specific amino acid targeting sequences (3-5) responsible for its localization to unique intracellular vesicular compartments found in adipocytes and muscle cells (6)(7)(8)(9)(10)(11). In response to acute insulin stimulation, these preformed GLUT4-containing vesicles rapidly translocate to the plasma membrane in a GTP-dependent process, resulting in a large increase in plasma membrane-associated GLUT4 protein (9-17).In contrast to this acute pathway of insulin action, catabolic states such as fasting and non-insulin-dependent diabetes are directly associated with a marked resistance of adipose and muscle tissue to insulin-stimulated glucose uptake (18)(19)(20). Recently, several studies have suggested that a decrease in GLUT4 expression may be the initial cause of insulin resistance in adipose tissue, which contributes to the maintenance ofinsulin resistance in muscle (21)(22)(23)(24)(25)(26)(27)(28)(29). Since the pathophysiological mechanisms responsible for insulin resistance are poorly understood, we have recently generated transgenic mice expressing high levels of the human GLUT4The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indi...

A MED13-dependent skeletal muscle gene program controls systemic glucose homeostasis and hepatic metabolism

“…These observations are in agreement with previous studies that reported enhanced glucose tolerance and insulin sensitivity in mice with a 1.3-fold increase of glycogen content in skeletal muscle due to enhanced glycogen synthesis (Patel et al 2008). Similarly, skeletal muscle from transgenic mice overexpressing Glut4 shows an increase in glycogen content accompanied by enhanced glucose tolerance and insulin sensitivity (Liu et al 1993). Although changes in expression of Glut4 and glycogen storage have been associated with enhanced glucose tolerance and insulin sensitivity, our study reveals for the first time the involvement of MED13 in skeletal muscle glucose metabolism and its impact on hepatic steatosis in the HFD-induced insulin-resistant state.…”

Glucose transport and sensing in the maintenance of glucose homeostasis and metabolic harmony

“…Similar to the muscle-specific GLUT1 overexpression model, transgenic mice overexpressing GLUT4 in both muscle and adipose tissue also show a marked reduction in fed and fasted glucose levels in addition to improved glucose tolerance (12). Similar to the muscle-specific GLUT1 overexpressors, muscle/fat-specific GLUT4 overexpressors also demonstrate increases in circulating lactate and b-hydroxybutyrate levels.…”

“…Similar to the muscle-specific GLUT1 overexpressors, muscle/fat-specific GLUT4 overexpressors also demonstrate increases in circulating lactate and b-hydroxybutyrate levels. In contrast to the musclespecific GLUT1 overexpressors, insulin levels are appropriately decreased in response to the basal hypoglycemia present in the muscle/fat-specific GLUT4 overexpressors (12). In addition, the muscle/fat-specific GLUT4 overexpressors demonstrate increased glucose disposal in response to insulin during a clamp, in contrast to the insulin resistance in muscle-specific GLUT1 overexpressors (11).…”

Glucose Metabolism in Mice Lacking Muscle Glycogen Synthase

“…Basal muscle glycogen levels in both models were normal but insulin-stimulated glycogen synthesis was reduced (22,(25)(26)(27). In contrast, transgenic mice overexpressing GLUT4 (28,29) and GLUT1 (28,30,31) in muscle had increased glucose uptake, increased muscle glycogen content, and improved glucose tolerance. This improvement in glucose tolerance occurred despite skeletal muscle insulin resistance as determined by euglycemichyperinsulinemic clamp (28) and in ex-vivo muscle studies (31,32).…”