Decreased Prorenin Processing Develops before Autonomic Dysfunction in Type 1 Diabetes

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Abstract
It is well documented that diabetic patients with chronic compli- cations have decreased renin secretion and elevations in the renin precursor prorenin. It is uncertain, however, whether the abnormal processing of prorenin is reflective of microvascular disease, hyper- tension, or autonomic neuropathy. Dechaux et al. (Transplant Proc. 18:1598 -1599, 1986) observed abnormalities in prorenin processing in uncomplicated diabetes and suggested that it was the result of subclinical autonomic neuropathy. To test this hypothesis, we mea- sured renin, prorenin, and autonomic function in early type 1 diabetes at a time when there is little or no microvascular disease or hyper- volemia. Thirty-seven patients (10 males, 27 females) enrolled 2-22 months after diagnosis in a longitudinal study in which renin, pro- renin, and autonomic function were measured annually for 3 years. Forty-one age-matched control subjects were also studied. PRA in the diabetic patients at the time of the second and third evaluations was 1.71 6 0.24 ng angiotensin I/mLzh and 1.67 6 0.24 ng angiotensin I/mLzh, respectively, significantly lower (P , 0.05) than that of the control subjects in whom PRA was 2.96 6 0.38 ng angiotensin I/mLzh. Prorenin was not different in the diabetic pa- tients in comparison with controls. The renin to prorenin ratio in the diabetic patients at the time of the first, second, and third evaluations was 0.260 6 0.03, 0.235 6 0.05, and 0.227 6 0.05, respectively, sig- nificantly lower (P , 0.01) than in control subjects in whom the renin to prorenin ratio was 0.475 6 0.08. Despite this, at the time of the first and second evaluations, there was no evidence of autonomic dysfunc- tion and no correlation between any test of autonomic function and the renin to prorenin ratio. At the time of the third evaluation, however, the intermediate frequency (0.04 - 0.15 Hz) power spectra while pa- tients were supine (an index of sympathetic modulation of heart rate variability) showed a highly significant (P , .001) correlation with the renin to prorenin ratio. High frequency (0.15- 0.40 Hz) spectra from supine patients at the third evaluation also correlated with the renin to prorenin ratio (P , 0.01). We conclude abnormal processing of prorenin develops in diabetic patients prior to microvascular disease, even before the first evidence of autonomic dysfunction. Although the latter may play a contributory role, additional as yet unidentified mechanisms seem to interrupt the processing of prorenin in early diabetes. (J Clin Endocrinol Metab 85: 585-589, 2000)

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