Pre-diabetes and sympathetic nervous system mediated microvascular dysregulation in skeletal muscle
Bibliographic record
Abstract
Pre-diabetes is associated with impairments in cardiovascular health that manifest prior to the onset of overt type 2 diabetes. Characterized by hyperinsulinemia and insulin resistance, pre-diabetes has been associated with increases in sympathetic nerve activity, which may result in augmented sympathetic control of the peripheral vasculature within skeletal muscle. Currently however, there are no studies investigating the impact of pre-diabetes on sympathetically-mediated vascular control. The primary study of this thesis investigated the effects of pre-diabetes on baseline sympathetic neuropeptide Y Y1 receptor (NPY Y1R) and alpha 1 adrenergic receptor (a1R) control of hindlimb vascular tone. Experiments were carried out in anesthetized pre-diabetic Zucker Diabetic Fatty (ZDF) rats and control lean ZDF rats during drug delivery of sympathetic antagonists while measuring femoral artery blood flow (Qfem) and calculated vascular conductance (VC). Despite similar baseline Qfem and VC, Y1R, a1R and dual Y1R+a1R blockade (via BIBP3226 and prazosin) elicited increases in Qfem and VC that were greater in pre-diabetic rats compared to controls, demonstrating heightened Y1R and a1R control of baseline vascular tone. These results were also supported by increased Y1R, a1R and NPY expression in hindlimb tissue of pre-diabetic rats. In effort to determine whether pre-diabetes effects microvascular network function in contracting skeletal muscle, intravital microscopy was used to evaluate arteriolar rapid onset vasodilation (ROV) and steady-state vasodilation and blood flow responses to tetanic and rhythmic contraction of the gluteus maximus muscle in pre-diabetic (The Pound Mouse, c57bl6 background) and control mice (c57bl6). Baseline diameter and blood flow of arterioles were similar between groups; however, contraction-evoked vasodilatory and blood flow responses were blunted in pre-diabetic compared to control mice. In addition, the magnitude of contraction-evoked dilation was greater in distal arterioles compared to proximal arterioles in GM arteriolar networks of control mice; however, such spatially-dependent differences in contraction-evoked dilation was disrupted in pre-diabetic mice. Blockade of Y1R and a1R (via BIBP3226 and prazosin) restored ROV and steady-state vasodilation to tetanic and rhythmic contractions in pre-diabetic mice to levels similar to controls. Blockade of arteriolar sympathetic receptors also restored dilatory magnitude of distal arterioles in pre-diabetic mice. In conclusion, the results presented in this dissertation provide evidence that peripheral arteriolar Y1R and a1R activation are enhanced in pre-diabetes, resulting in augmented sympathetic modulation of basal skeletal muscle blood flow and VC, as well as deficits in arteriolar vasodilation to skeletal muscle contraction.
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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) | 0.000 | 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) | 0.005 | 0.000 |
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".