/fh: term " insulin resistant " has generally been applied /to those diabetics whose daily insulin requirement ? exceeds 200 units. Such diabetics are relatively rare ; l Kleeberg, Diengott, and Gottfried (1956) found only ? soms 50 instances in the literature. The purpose of this j paper is to report the results of immunological and l other studies on an additional 13 cases, 6 of them treated with prednisone. The factors responsible for insulin resistance are not rknown with certainty, but include certain hormones and Mother substances in the serum, some of which have the 'properties of antibody and others which are of a ^different nature. The ability of serum from insulin resistant diabetic patients to protect animals from the hypoglycaemic action of insulin was demonstrated in rabbits by Glen and Eaton (1938) and in mice by Lowell (1942), who developed the mouse-convulsion test. Marsh and Haugaard (1952), using the rat-diaphragm technique described by Stadie et al. (1949), reported ; insulin inhibition by sera from normal patients, from imild diabetics, and, to a much greater degree, from three f severely insulin-resistant diabetics. Using a similar [diaphragm technique, Field and Stetten (1956) were able ?to demonstrate the presence of an insulin antagonist in , the alpha-globulin fraction of diabetics with severe Iketosis, and Vallance-Owen, Dennes, and Campbell [(1958) in the albumin fraction of plasma from uncontrolled insulin-requiring diabetics and also from j normal subjects. For various reasons insulin has been regarded as poorly antigenic, but successful immunization in rabbits has been reported by Wasserman, Broh-Kahn, and Mirsky (1940), and also by Moloney and Coval (1955), [who produced immune serum in guinea-pigs, using cattle and pig insulin as antigens. Berson et al. (1956) have shown that, in almost all human subjects receiving exogenous insulin, antibodies capable of binding insulin in vivo and in vitro soon appear. It would seem, therefore, that the difference between insulin resistance and non-resistance in insulin-treated patients may be essentially a quantitative one. In this connexion the work of Berson and Yalow (1957) suggests that the total 'insulin-binding capacity of sera from non-resistant treated subjects is of the order of 10 units per litre of ' plasma, whereas binding capacities of as much as 500 units per litre of plasma were found in sera from insulin 1 resistant patients. In 1938 Glen and Eaton reported the case of a severely insulin-resistant girl whose insulin requirement fell after the administration of oestrogen, but, apart from this isolated instance, until recently no effective method of treatment has been described. Fortunately, perseverance with large doses of insulin has in most cases been followed by a spontaneous fall in insulin requirement to a much lower but still usually fairly high figure. Collens and Banowitch (1955) reported the case of a severely insulin-resistant diabetic whose daily insulin requirement subsequently fell from 1,000 to 200 units when given cortisone in large doses. Colwell and Weiger (1956), using corticotrophin, obtained an even more spectacular reduction of insulin requirement from 11,400 to 100 units in a case of haemochromatosis. Similar responses to corticotrophin have been reported by Kleeberg, Diengott, and Gottfried (1956) and by Gitelson and Wislicki (1956). Methods