Abstract 308: Rgs2 Is An Endogenous Inhibitor Of Insulin Signaling
Bibliographic record
Abstract
Background: Insulin resistance is the hallmark of type 2 diabetes and is a known risk factor for the development of cardiovascular diseases. We have determined that overexpression of a GTPase-activating protein, RGS2 decreases insulin sensitivity. This study describes RGS2 regulation of insulin signaling pathways in order to assess whether this information can be used to reverse insulin insensitivity in diabetes. Hypothesis, Methods and Results: RGS2 protein levels were elevated 3 to 5-fold in white adipose tissues from ob/ob and high fat diet induced Insulin Resistant mice. Further, RGS2 protein is elevated in insulin resistant 3T3-L1 adipocytes treated chronically with either insulin, ET-1, or TNF-aplha. Further, SiRNA knockdown of endogenous RGS2 protein increases basal, insulin independent and insulin-dependent GLUT4 translocation. We hypothesized that the RGS2 regulatory system is defective/overactive in insulin resistance, and that a modulation of this regulatory system by RGS2 inhibition would improve insulin sensitivity. Thus, we determined the mechanisms whereby RGS2 modulates insulin sensitivity in 3T3-L1 adipocytes; focusing on insulin-regulated G-protein/PI3-K pathways leading to GLUT4 translocation and glucose uptake; utilizing adenoviruses over-expressing wild-type and mutants RGS2, as well as by siRNA-mediated knock down of endogenous RGS2. We overexpressed the Wild-Type (WT), GTPase defective (GD), and plasma membrane translocation defective (TD) RGS2 proteins in 3T3-L1 adipocytes. Overexpression of WT RGS2 leads to ~ 50% inhibition of insulin induced 2-DOG uptake, without affecting IR Tyr phosphorylation. RGS2 constitutively associates with Galpha/q11, and prevent its Tyr phosphorylation and activation by insulin. Interestingly, insulin-stimulated PKClambda phosphorylation was completely blocked by RGS2, whereas, AKT phosphorylation was minimally inhibited. Neither the insulin receptor tyrosine phosphorylation nor insulin-stimulated MAPK phosphorylation was affected by RGS2. Conclusion: This study identifies a novel role of RGS2 in cellular insulin resistance by negatively regulating signaling through the Galpha/q11 pathway to glucose uptake. This research has received full or partial funding support from the American Heart Association, AHA Western States Affiliate (California, Nevada & Utah).
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.008 | 0.004 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".