Metalloproteinases Damage the Insulin Receptor to Cause Insulin Resistance in Spontaneously Hypertensive Rats

We performed euglycemic clamp studies with labeled glucose to measure insulin's effect on hepatic glucose output (HGO) and peripheral glucose clearance in eight conscious mobile spontaneously hypertensive rats (SHR) and eleven normotensive Wistar-Kyoto (WKY) rats age 9-10 wk. Systolic blood pressure was elevated in the SHR (P less than 0.001), whereas means of 12-h-fasted plasma insulin (P greater than 0.4), glucose (P greater than 0.07), HGO (P greater than 0.25), and glucose clearance (P greater than 0.2) did not differ significantly between groups. Infusions of human insulin into SHR and WKY rats (1 and 1.5 mU.min-1.kg-1, respectively) during concomitant somatostatin administration reestablished basal insulinemia in both groups. Neither HGO (P greater than 0.15) nor glucose clearance (P greater than 0.3) differed significantly between SHR and WKY rats under those conditions. Somatostatin plus higher-dose insulin infusions (4 mU.min-1.kg-1 in SHR and 3 or 6 mU.min-1.kg-1 in WKY rats) resulted in physiological hyperinsulinemia in all rats. Insulin sensitivity, calculated as the increase in glucose clearance effected by an increase in circulating insulin during higher-dose insulin infusions, did not differ significantly between SHR and WKY groups (P greater than 0.3). HGO was completely suppressed in SHR and WKY rats during the higher-dose insulin infusions. Our data indicate that hypertension is present in SHR at an age when insulin-mediated glucose disposal is not different from age-matched WKY rats. These findings do not support a role for peripheral insulin resistance in the genesis of hypertension in SHR.

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Voluntary running improves glucose tolerance and insulin resistance in female spontaneously hypertensive rats

American Journal of Hypertension ◽

10.1016/s0895-7061(01)01285-7 ◽

2001 ◽

Vol 14 (7) ◽

pp. 708-715 ◽

Cited By ~ 14

Author(s):

T Kinney LaPier

Keyword(s):

Insulin Resistance ◽

Glucose Tolerance ◽

Spontaneously Hypertensive Rats ◽

Hypertensive Rats ◽

Spontaneously Hypertensive ◽

Voluntary Running

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Improvement of vascular insulin sensitivity by downregulation of GRK2 mediates exercise-induced alleviation of hypertension in spontaneously hypertensive rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00290.2013 ◽

2013 ◽

Vol 305 (8) ◽

pp. H1111-H1119 ◽

Cited By ~ 23

Author(s):

Wenjuan Xing ◽

Youyou Li ◽

Haifeng Zhang ◽

Chunjuan Mi ◽

Zuoxu Hou ◽

...

Keyword(s):

Insulin Resistance ◽

Blood Pressure ◽

Insulin Sensitivity ◽

Spontaneously Hypertensive Rats ◽

Hypertensive Rats ◽

Spontaneously Hypertensive ◽

Exercise Induced ◽

Grk2 Expression ◽

Expression And Activity

Exercise training lowers blood pressure and is a recommended nonpharmacological strategy and useful adjunctive therapy for hypertensive patients. Studies demonstrate that physical activity attenuates progression of hypertension. However, underlying mechanisms remain elusive. Vascular insulin resistance and endothelial dysfunction plays a critical role in the development of hypertension. The present study investigated whether long-term physical exercise starting during the prehypertensive period prevents the development of hypertension via improving vascular insulin sensitivity. Young (4 wk old) prehypertensive spontaneously hypertensive rats (SHRs) and their normotensive Wistar-Kyoto (WKY) control rats were subjected to a 10-wk free-of-loading swim training session (60 min/day, 5 days/wk). Blood pressure, mesenteric arteriolar vasorelaxation, G protein-coupled receptor kinase-2 (GRK2) expression and activity, and insulin-stimulated Akt/endothelial nitric oxide synthase (eNOS) activation were determined. SHRs had higher systolic blood pressure, systemic insulin resistance, and impaired vasodilator actions of insulin in resistance vessels when compared with WKY rats. Systolic blood pressure in SHRs postexercise was significantly lower than that in sedentary rats. Vascular insulin sensitivity in mesenteric arteries was improved after exercise training as evidenced by an increased vasodilator response to insulin. In addition, exercise downregulated vascular GRK2 expression and activity, which further increased insulin-stimulated vascular Akt/eNOS activation in exercised SHRs. Specific small interfering RNA knockdown of GRK2 in endothelium mimicked the effect of exercise-enhanced vascular insulin sensitivity. Likewise, upregulation of GRK2 by Chariot-mediated delivery opposed exercise-induced vascular insulin sensitization. Taken together, our results suggest that long-term exercise beginning at the prehypertensive stage improves vascular insulin sensitivity via downregulation of vascular GRK2 that may help to limit the progression of hypertension.

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