Hypoglycemic effects of insulin-like growth factor-1 in experimental uremia: can concomitant growth hormone administration prevent this effect?
Kovacs GT, Worgall S, Schwalbach P, Steichele T, Mehls O, Rosivall L.
2nd Department of Pediatrics and Institute of Patophysiology and International Nephrological Research and Training Center, Semmelweis University, Budapest, Hungary.
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The risk of hypoglycemia limits the clinical application of insulin-like growth factor-1 (IGF-1). Our studies aimed to evaluate the mode of occurrence as well as the prevention of this side effect. Acute administration (i.v. infusion) of IGF-1 in subtotal nephrectomized uremic (U), sham-operated ad libitum fed control (C) and sham-operated pair-fed control (P) rats led to hypoglycemia, though more expressed in P. Serum glucose levels decreased within 60 min after the IGF-1 administration by 40% in U, by 45% in C and by 52% in P (p < 0.05, U vs. P). Chronic administration (7 days) of 1, 4 and 8 mg/kg/day IGF-1 in U rats led to hypoglycemia in an increasing manner as the dose of IGF-1 increased. On the first day, 2 h after injection, serum glucose levels were 116.5 +/- 8.6, 110.4 +/- 12.4, 60,3 +/- 19.2 and 50.6 +/- 18.3 mg/dl, respectively (p < 0. 01). One week later, IGF-1 therapy proved to be less hypoglycemic in all the groups. On day 7, 2 h after injection the serum glucose levels were 118.9 +/- 23.8, 89.0 +/- 23.9 and 66.0 +/- 32.0, respectively (in comparison to day 1 for 4 and 8 mg/kg/day IGF-1 p < 0.05). The combined effect of 4 mg/kg/day IGF-1 and 10 IU/kg/day growth hormone (GH) was also studied in U and P animals. Two hours after the first injections of IGF-1 serum glucose levels decreased in U from 120.0 +/- 11.3 to 49.2 +/- 21.6 mg/dl, while IGF-1 plus GH decreased the glucose level from 122.0 +/- 15.5 to 81.3 +/- 24.7 mg/dl (p < 0.05 IGF-1 vs. IGF-1 + GH). The hypoglycemic effect of IGF-1 was less expressed by long-term treatment and simultaneous administration of GH overcame the glucose-lowering effect of IGF-1 (serum glucose levels on day 11 one hour after the injections: 73.7 +/- 15.3 mg/dl with IGF-1, and 111.0 +/- 7.8 mg/dl with IGF-1 + GH). Methylprednisolone (MP) did not significantly alter the former effects of IGF-1 and GH. In summary, IGF-1 leads to hypoglycemia in control and uremic rats in a dose-dependent manner. This effect becomes less expressed after prolonged administration. GH attenuates the hypoglycemic effect of IGF-1. This suggests that the combined GH and IGF-1 treatment is more effective and less dangerous in correcting uremic growth failure.
