Submitted on July 31, 2007
Accepted on October 1, 2007
SKELETAL MUSCLE CAPILLARY RESPONSES TO INSULIN ARE ABNORMAL IN LATE-STAGE DIABETES AND ARE RESTORED BY ANGIOGENSIN CONVERTING ENZYME INHIBITION
Lucy H Clerk1, Michelle A Vincent1, Eugene Barrett2, Miles F Lankford1, and Jonathan R. Lindner3*
1 University of Virginia, Charlottesville, Virginia, United States
2 Endocrinology and Metabolism, University of Virginia, 450 Ray C Hunt Dr, Charlottesville, Virginia, 22908, United States
3 Cardiovascular Division, Oregon Health & Science University, Portland, Oregon, United States
* To whom correspondence should be addressed. E-mail: lindnerj{at}ohsu.edu.
Acute physiologic hyperinsulinemia increases skeletal muscle capillary blood volume (CBV), presumably in order to augment glucose and insulin delivery. We hypothesized that insulin-mediated changes in CBV are impaired in type-2 diabetes mellitus (DM) and are improved by angiotensin converting enzyme inhibition (ACE-I). Zucker obese diabetic rats (ZDF, n=18) and control rats (n=9) were studied at 20 weeks of age. Half of the ZDF rats were treated with quinapril (ZDF-Q) for 15 weeks prior to study. CBV and capillary flow in hindlimb skeletal muscle were measured by contrast-enhanced ultrasound (CEU) at baseline, and at 30 and 120 min after initiation of a euglycemic hyperinsulinemic clamp (3 mU/min/kg). At baseline, ZDF and ZDF-Q rats were hyperglycemic and hyperinsulinemic versus controls. Glucose utilization in ZDF rats was 60-70% lower (p<0.05) than in controls after 30 and 120 min of hyperinsulinemia. In ZDF-Q rats, glucose utilization was impaired at 30 min but similar to controls at 120 min. Basal CBV was lower in ZDF and ZDF-Q rats compared to controls (13±4, 7±3 and 9±2 units, respectively). With hyperinsulinemia, CBV increased by about 2-fold in control animals at 30 and 120 min, did not change in ZDF animals, and increased in ZDF-Q animals only at 120 min to a level similar to controls. Anatomic capillary density on immunohistology was not different between groups. We conclude that insulin-mediated capillary recruitment in skeletal muscle, which participates in glucose utilization, is impaired in animals with DM and can be partially reversed by chronic ACE-I therapy.
