Evidence has accumulated suggesting that the state of secondary hyperparathyroidism and the elevated blood levels of parathyroid hormone (PTH) in uremia participate in the genesis of many uremic manifestations. The present study examined the role of PTH in glucose intolerance of chronic renal failure (CRF). Intravenous glucose tolerance tests (IVGTT) and euglycemic and hyperglycemic clamp studies were performed in dogs with CRF with (NPX) and without parathyroid glands (NPX-PTX). There were no significant differences among the plasma concentrations of electrolytes, degree of CRF, and its duration. The serum levels of PTH were elevated in NPX and undetectable in NPX-PTX. The NPX dogs displayed glucose intolerance after CRF and blood glucose concentrations during IVGTT were significantly (P < 0.01) higher than corresponding values before CRF. In contrast, blood glucose levels after IVGTT in NPX-PTX before and after CRF were not different. K-g rate fell after CRF from 2.86 ± 0.48 to 1.23 ± 0.18%/min (P < 0.01) in NPX but remained unchanged in NPX-PTX (from 2.41 ± 0.43 to 2.86 ± 0.86%/min) dogs. Blood insulin levels after IVGTT in NPX-PTX were more than twice higher than in NPX animals (P < 0.01) and for any given level of blood glucose concentration, the insulin levels were higher in NPX-PTX than NPX dogs. Clamp studies showed that the total amount of glucose utilized was significantly lower (P < 0.025) in NPX (6.64 ± 1.13 mg/kg · min) than in NPX-PTX (10.74 ± 1.1 mg/kg · min) dogs. The early, late, and total insulin responses were significantly (P < 0.025) greater in the NPX-PTX than NPX animals. The values for the total response were 143 ± 28 vs. 71 ± 10 μU/ml, P < 0.01. There was no significant difference in the ratio of glucose metabolized to the total insulin response, a measure of tissue sensitivity to insulin, between the two groups. The glucose metabolized to total insulin response ratio in NPX (5.12 ± 0.76 mg/kg · min per μU/ml) and NPX-PTX (5.18 ± 0.57 mg/kg · min per μU/ml) dogs was not different but significantly (P < 0.01) lower than in normal animals (9.98 ± 1.26 mg/kg · min per μU/ml). The metabolic clearance rate of insulin was significantly (P < 0.02) reduced in both NPX (12.1 ± 0.7 ml/kg · min) dogs, as compared with normal animals (17.4 ± 1.8 ml/kg · min). The basal hepatic glucose production was similar in both groups of animals and not different from normal dogs; both the time course and the magnitude of suppression of hepatic glucose production by insulin were similar in both groups. There were no differences in the binding affinity, binding sites concentration, and binding capacity of monocytes to insulin among NPX, NPX-PTX, and normal dogs. The data show that (a) glucose intolerance does not develop with CRF in the absence of PTH, (b) PTH does not affect metabolic clearance of insulin or tissue resistance to insulin in CRF, and (c) the normalization of glucose metabolism in CRF in the absence of PTH is due to increased insulin secretion. The results indicate that excess PTH in CRF interferes with the ability of the β-cells to augment insulin secretion appropriately in response to the insulin-resistant state.
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