Elevation in Tanis Expression Alters Glucose Metabolism and Insulin Sensitivity in H4IIE Cells

Abstract

Increased hepatic glucose output and decreased glucose utilization are implicated in the development of type 2 diabetes. We previously reported that the expression of a novel gene, Tanis, was upregulated in the liver during fasting in the obese/diabetic animal model Psammomys obesus. Here, we have further studied the protein and its function. Cell fractionation indicated that Tanis was localized in the plasma membrane and microsomes but not in the nucleus, mitochondria, or soluble protein fraction. Consistent with previous gene expression data, hepatic Tanis protein levels increased more significantly in diabetic P. obesus than in nondiabetic controls after fasting. We used a recombinant adenovirus to increase Tanis expression in hepatoma H4IIE cells and investigated its role in metabolism. Tanis overexpression reduced glucose uptake, basal and insulin-stimulated glycogen synthesis, and glycogen content and attenuated the suppression of PEPCK gene expression by insulin, but it did not affect insulin-stimulated insulin receptor phosphorylation or triglyceride synthesis. These results suggest that Tanis may be involved in the regulation of glucose metabolism, and increased expression of Tanis could contribute to insulin resistance in the liver. Diabetes 52:929 -934, 2003 A major factor that contributes to hyperglycemia in type 2 diabetes is excessive hepatic glucose production. Depending on the concentrations of insulin and glucagon in the portal blood and the level of glucose itself, the liver either stores glucose in the form of glycogen or, upon the depletion of glycogen, synthesizes glucose via the gluconeogenic pathway for export. In many subjects with type 2 diabetes, hepatic glucose utilization, associated with reduced glucokinase activity, is diminished (1). Furthermore, insulin is less effective in suppressing gluconeogenesis in these subjects, leading to elevated hepatic glucose output (2,3). The implication of these defects in the development of hyperglycemia has been supported by studies of transgenic mice that overexpress hepatic PEPCK or glucose-6-phosphatase. A modest increase in their activities (two-to threefold) caused hyperglycemia, hyperinsulinemia, impaired glucose tolerance, and decreased glycogen storage (4 -6). Conversely, increased hepatic glucose utilization through glucokinase overexpression lowered plasma glucose concentration, improved insulin sensitivity, and increased glycogen storage in rats (7,8). These findings strongly suggest a critical role of the liver in maintaining glucose homeostasis.As both genetic and environmental factors play a role in the development of type 2 diabetes (9), we have used a polygenic animal model, Psammomys obesus (Israeli sand rat), to identify genes that may contribute to its pathogenesis. When housed in the laboratory and maintained on an ad libitum diet of standard rodent food, a proportion of the animals spontaneously develop metabolic abnormalities, including obesity and type 2 diabetes (10 -12). The distributions of body weight, blood glucose, and...

Relationship Between Serum Amyloid A Level andTanis/SelSmRNA Expression in Skeletal Muscle and Adipose Tissue From Healthy and Type 2 Diabetic Subjects

“…Tanis encodes a 189 -amino acid protein and contains a putative transmembrane domain. Tanis is primarily localized to plasma and microsomal membranes (6). Tanis is highly expressed in three primary insulin target tissues: liver, adipose, and skeletal muscle (5), suggesting a putative role in modulating insulin action and/or glucose metabolism.…”

“…In vitro experiments reveal that expression of Tanis in 3T3 L1 adipocytes is decreased following exposure to high concentrations of insulin and glucose. Furthermore, overexpression of Tanis in hepatoma H4IIE cells is associated with reduced glucose uptake, glycogen synthesis, and glycogen content, as well as impairment of the ability of insulin to suppress expression of the phosphoenolpyruvate carboxykinase (PEPCK) gene (6).…”

A paradox: Insulin inhibits expression and secretion of resistin which induces insulin resistance

“…Hepatocytes and myotubes are two important targets of insulin [21] . Glycogen synthesis in insulin-stimulated hepatocytes is the most important marker of hepatocyte insulin sensitivity [22] . After treatment with resistin for 2 h, basal glycogen synthesis decreased about 15% and insulinstimulated glycogen synthesis decreased about 25% in H4IIE cells (P < 0.05, Figure 3A).…”

Upregulation of Tanis mRNA Expression in the Liver is Associated with Insulin Resistance in Rats

“…Inflammatory factors in serum of patients, such as C-reactive protein (CRP), interleukin-6 (IL-6) and plasminogen activator inhibitor-1 (PAI-1), are significantly correlated with hyperglycemia, impaired glucose tolerance and decreased insulin sensitivity (Pradhan et al 2001;Gao et al 2003).…”

“…Tanis is predominately localized in the endoplasmic reticulum and cell surface (Gao et al 2003). Recently, Tanis has been identified as a novel hepatic receptor for serum amyloid A (SAA) that is regulated by glucose and differentially expressed in Psamommys obesus, an animal model of type 2 diabetes and the metabolic syndrome (Walder et al 2002).…”