A highly purified growth hormone preparation (Wilhelmi) was tested for its hypoglycemic activity in four fasting, hypophysectomized–depancreatized dogs (Houssay dogs) maintained without exogenous insulin for 2–4 weeks. A single intravenous injection of growth hormone, 5 mg per kg body weight, had no effect on blood sugar over a period of 6 hours. It was concluded that highly purified growth hormone has no hypoglycemic effect in the absence of biologically active insulin.
Serum insulin-like activity was measured serially by the epididymal fat pad method in twelve dogs over several weeks. The animals were first hypophysectomized and subsequently pancreatectomized; no insulin was administered at any stage of the experiment. Hypophysectomy resulted in a reduction of serum ILA of some 50 per cent from an average normal fasting value of 420 μU. per ml.
Subsequent pancreatectomy caused no further appreciable reduction in serum ILA over the entire observation period of five weeks. In a selected number of serum samples residual ILA was detectable also by the rat hemidiaphragin procedure. None of the Houssay dogs had measurable amounts of insulin in blood by immunoassay. It was considered unlikely that activities measured by the two bio-assays represented insulin.
The binding affinity of sulphated insulin compared with unmodified, neutral insulin has been reported to be approximately four times lower in human and rat adipocytes but over twenty times lower in rat hepatocytes. In the present study the biological action of sulphated insulin was assessed in rat hepatocytes and human and rat adipocytes. To achieve half-maximal stimulation of fatty acid synthesis in rat hepatocytes about twenty one times higher concentrations of sulphated than neutral insulin were required (15.07 +/- 5.50 vs 0.71 +/- 0.34 nmol/l), this ratio being similar to the ratio of binding affinity in rat hepatocytes. In human adipocytes, half-maximal stimulation of initial rates of glucose uptake was observed at 11.6 +/- 5.1 vs 2.9 +/- 1.3 pmol/l for sulphated and neutral insulin respectively, and half-maximal inhibition of lipolysis at 31.0 +/- 13.5 vs 7.3 +/- 2.5 pmol/l respectively. These data are consistent with the four-fold lower binding affinity of sulphated insulin to human adipocytes. However, in rat adipocytes the biological potency of sulphated insulin was found to be much lower than anticipated from the binding data, half-maximal stimulation of initial rates of glucose uptake being observed at 757 +/- 299 vs 35 +/- 13 pmol/l respectively and half-maximal inhibition of lipolysis at 35.9 +/- 12.1 vs 1.5 +/- 0.5 pmol/l respectively. Thus, in rat adipocytes, approximately 22 times the concentration of sulphated insulin was required to achieve equivalent biological effect. A discrepancy between binding affinity and biological action with respect to sulphated insulin was identified in rat adipocytes but not human adipocytes nor rat hepatocytes suggesting differences in the binding-action linkage in these cells.
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