The first significant advance in insulin modifications since the introduction of isophane (NPH) insulin, a crystalline modification of protamine zinc insulin, was the development of so-called insulin-zinc suspensions by Hallas-Møller and co-workers of the Novo Laboratories, Copenhagen, in 1952.1 Indeed, the rather startling revelation that zinc alone is capable of extending the time-action curve of insulin had eluded competent investigators for many years, simply because it was not fully realized that such delayed action is actually a fourfold function of a suitable buffer (acetate), a critical pH range (pH 5-8), the quantity of zinc present (not less than 0.5 mg. of zinc per 1,000 units of insulin), and the physical state of the insulin (amorphous and crystalline [large or small crystals]).
The commonly used phosphate buffer has been the major deterrent to prolongation of insulin action by zinc alone, even in the presence of large concentrations of zinc. In
Haunz EA. CLINICAL EVALUATION OF LENTE INSULIN IN ONE HUNDRED NINE DIABETIC PATIENTS. JAMA. 1955;159(17):1611–1618. doi:10.1001/jama.1955.02960340031008
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