Regulation of Endogenous Glucose Production in Glucose Transporter 4 Over-Expressing Mice

Abstract

Strategies to amplify whole-body glucose disposal are key therapies to treat type 2 diabetes. Mice that over-express glucose transporter 4 (Glut4) in skeletal muscle, heart, and adipose tissue (G4Tg) exhibit increased fasting glucose disposal and thus lowered blood glucose. Intriguingly, G4Tg mice also exhibit improved insulin-stimulated suppression of endogenous glucose production even though Glut4 is not present in the liver. It is unclear, however, if hepatic gluco-regulation is altered in G4Tg mice in the basal, non-insulin-stimulated state. The current studies were performed to examine fasting hepatic glucose metabolism in G4Tg mice and to determine whether gluco-regulatory adaptations exist in the non-insulin-stimulated condition. To test this question, phloridzin-glucose clamps were used to match blood glucose and pancreatic hormone levels while tracer dilution techniques were used to measure glucose flux. These techniques were performed in chronically-catheterized, conscious, and un-stressed 5h-fasted G4Tg and wild-type (WT) littermates. Results show reduced blood glucose, hepatic glycogen content, and hepatic glucokinase (GK) activity/expression as well as higher endogenous glucose production, glucose disposal, arterial glucagon, and hepatic glucose-6-phosphatase (G6Pase) activity/expression in G4Tg mice versus WT controls. Clamping blood glucose for 90 min at ∼115 mg/dLin G4Tg and WT mice normalized nearly all variables. Notably, however, net hepatic glycogen synthetic rates were disproportionately elevated compared to changes in blood glucose. In conclusion, these studies demonstrate that basal improvements in glucose tolerance due to increased uptake in extra-hepatic sites provoke important gluco-regulatory adaptations in the liver. Although changes in blood glucose underlie the majority of these adaptations, net hepatic glycogen synthesis is sensitized. These data emphasize that anti-diabetic therapies that target skeletal muscle, heart, and/or adipose tissue likely positively impact the liver.

Maternal periodontitis decreases plasma membrane GLUT4 content in skeletal muscle of adult offspring

“…Defects in glucose regulation define type-2 diabetes [39] and inflammatory cytokines, such as TNF-α, are elevated in the adult offspring of rats with PD [12]. These results are in agreement with this study.…”

High-Fat Diet-Induced Complement Activation Mediates Intestinal Inflammation and Neoplasia, Independent of Obesity

“…Fasting glucose was measured with an OneTouch Ultra glucometer (Life Scan, Inc., Milpitas, CA). Homeostatic model assessment of insulin resistance (HOMA-IR) (21, 22) was calculated using fasting insulin and glucose levels [HOMA-IR = fasting insulin (pmol/L) x fasting blood glucose (mmol/L) /22.5]. Leptin, adiponectin, and complement C5a were measured in plasma with ELISA kits from EMD Millipore (leptin and adiponectin; Temecula, CA) and R&D Systems (C5a; Minneapolis, MN).…”

Glucose metabolic abnormality is associated with defective mineral homeostasis in skeletal disorder mouse model

“…We did not measure G6Pase activity in PUG mice. If hepatic G6Pase activity was upregulated, we speculated the reason might be a feedback effect aiming to reverse the abnormal glucose metabolism according to published reports [43]. Moreover, blood glucose homeostasis could be regulated by other different signaling.…”

“…Moreover, blood glucose homeostasis could be regulated by other different signaling. Several studies show that blood glucose could be modulated by intestine G6PC activity [44], glucose transportation [43] and glucose uptake [45], resulting in irrelevance between plasma glucose level and hepatic G6Pase activity. In XLH mouse model, decreased renal glucose reabsorption activity is also considered contributory to the decreased blood glucose [22].…”