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A B S T R A C T The role of skin and muscle vascular beds in baroreceptor-mediated alterations of peripheral vascular resistance was evaluated in six normal s jects in whom the skin circulation in one forearm was temporarily suppressed by epinephrine iontophoris. Baroreceptor activity was enhanced by application of negative pressure to the neck (neck suction) and inhibited by application of lower body negative pressure. Forearm blood flow was measured simultaneously in both arms with strain gauge plethysmographs. Since blood flow in the treated arm consisted entirely of muscle flow, skin flow was calculated from the difference between total forearm flow in the intact arm and muscle flow in the treated arm. Vascular resistances were calculated as the ratio of mean arterial pressure to the blood flow of each vascular bed. During neck suction, mean arterial pressure decreased from an average of 89 to 75 mm of Hg (P < 0.005), heart rate decreased from an average of 60 to 55 beats/min (P < 0.005), and total skin and muscle flows remained essentially unchanged. Cutaneous vascular resistance decreased from an average of 75 to 49 mm of Hg/ml per 100 g per min (P < 0.05), muscle vascular resistance from 68 to 51 (P < 0.005), and total forearm vascular resistance from 36 to 24 (P < 0.025). During lower body negative pressure,, heart rate increased from an average of 59 to 69 beats/min (P < 0.005), mean arterial pressure did not change significantly, and significant decreases occurred in forearm blood flow from 5.4 to 2.7 ml/100 g per min, in skin blood flow from 3.1 to 1.4, and in muscle blood flow from 2.3 to 1.3. Cutaneous vascular resistance increased from an average of 47 to 110 mm of Hg/ml per 100 g per min (P < 0.05), muscle vascular resistance from 43 to 72 (P <0.005), and total forearm vascular resistance from 20 to 38 (P <0.001). These results demonstrate

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Observational studies have shown that elevated systolic blood pressure (SBP) is associated with future onset of type 2 diabetes, but whether this association is causal is not known. We applied the Mendelian randomization framework to evaluate the causal hypothesis that elevated SBP increases risk for type 2 diabetes. We used 28 genetic variants associated with SBP and evaluated their impact on type 2 diabetes using a European-centric meta-analysis comprising 37,293 case and 125,686 control subjects. We found that elevation of SBP levels by 1 mmHg due to our genetic score was associated with a 2% increase in risk of type 2 diabetes (odds ratio 1.02, 95% CI 1.01–1.03, P = 9.05 × 10−5). To limit confounding, we constructed a second score based on 13 variants exclusively associated with SBP and found a similar increase in type 2 diabetes risk per 1 mmHg of genetic elevation in SBP (odds ratio 1.02, 95% CI 1.01–1.03, P = 1.48 × 10−3). Sensitivity analyses using multiple, alternative causal inference measures and simulation studies demonstrated consistent association, suggesting robustness of our primary observation. In line with previous reports from observational studies, we found that genetically elevated SBP was associated with increased risk for type 2 diabetes. Further work will be required to elucidate the biological mechanism and translational implications.