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Islet cell antibodies (ICA) were detected in 168 (33%) of 504 patients with insulin-dependent diabetes mellitus (IDDM). Mean age of onset of IDDM was 8.6 +/- 0.2 yr and mean age at testing was 13.4 +/- 0.3 yr. None of 162 controls without diabetes (mean age 21.8 +/- 0.9 yr) had ICA. Caucasian patients (404) had a 74% frequency of ICA within 3 mo of diagnosis and an overall ICA frequency of 36%. These results were similar to those reported from Europe. Black patients (100) had lower frequencies of ICA (P < 0.01) and thyroid antibodies (P < 0.05). Caucasian patients with onset of IDDM before 5 yr of age (107) had a lower frequency (P < 0.01) of ICA (21%) than those (297) with a later age of onset (42%). Patients with persistent ICA beyond 5 yr of IDDM had increased frequencies of gastric parietal and adrenal cortex cell antibodies. Thyroid microsomal antibodies were less frequent (P < 0.05) in blacks (4%) than in Caucasians (20%). The former did not have adrenal antibodies. Similar ICA frequencies among Caucasians with IDDM in the U.S. and in Europe suggest that etiologic factors are similar in the two geographic regions. The lower frequencies of ICA in patients with IDDM onset before 5 yr of age suggest that some of these patients may have a different etiology and/or a more rapid disappearance of islet cell antigens than patients with a later onset.l The lower ICA frequencies in black patients can be explained by heterogeneity of IDDM in this group and by admixture of IDDM susceptibility genes from the Caucasian genome to the black genome.

Male mice are more sensitive to the diabetogenic effect of streptozotocin (SZ) than female mice. These studies were designed to determine whether sex hormones could be responsible.A single intraperitoneal (i.p.) dose of 80 mg SZ/kg regularly induced acute severe diabetes in 45 day old male CD-1 mice beginning after 1 day, whereas females of the same age and strain remained euglycemic for 75 days after the same SZ dose. With 120 mg SZ/kg, similar female mice developed a mild, delayed hyperglycemia 41 days after injection. Inbred strains (DBA/2J) demonstrated a similar sex relationship.In 45 day old male CD-1 mice, pretreatments with antiandrogen (SCH.13521) reduced the hyperglycemic effect of SZ when compared with control male mice given the same SZ dose (P < 0.001). Castration of male CD-1 mice before SZ also caused a milder hyperglycemia than in sham-operated control mice (P < 0.001). Pretreatment with estrogens before SZ in male CD-1 mice had little effect.Female CD-1 mice, given 10 mg testosterone twice before the 120 mg SZ/kg injection, showed an increased sensitivity to SZ-induced diabetes when compared with female control mice or with female mice pretreated with only 1 mg testosterone (P < 0.001). Examination of the pancreases of these animals showed that the testosterone effect was accompanied by enhanced ft cell destruction and increased and more centrally placed a cells within islets.Phenobarbital when given daily for 7 days before the SZ injection potentiated the diabetogenic effect of SZ in male CD-1 mice and in female mice.These studies are consistent with an important action of testosterone in potentiating the pancreatic /3 cell toxicity of SZ. The similar synergistic effect of phenobarbital may help to clarify the biochemical mechanism of SZ-induced pancreatic /3 cell destruction. DIABETES 29:710-716, September 1980. S treptozotocin (SZ) is a broad spectrum antibioticpresent in isolates from cultures of Streptomyces achromogenes 1 which induces selective pancreatic /3 cell destruction and diabetes in a number of animal species. 2 " 7 We have shown that the severity and the time of onset of the hyperglycemia after SZ is a function of the dose used, the age of the animal, and the species. 8 The mechanism of action of SZ, which has been structurally characterized as 2-desoxy-2-(3'methyl-3'nitrosurea)-D glucopyranose, 9 remains unknown. It has been suggested that SZ may have a direct cytotoxic effect on the /3 cell membrane. 10 " 13 However, more evidence supports an intracellular mechanism, with depletion of nicotinamide adenine dinucleotide (NAD), as the basis for /3 cell damage. 14 " 18 SZ is an alkylating compound. The methylation of nicotinamide, by action of SZ, could lead to nonutilizable NAD precursors and a deprivation of useful NAD in the /3 cells. 19 The entry of SZ into /8 cells depends on its glucose moiety, and its uptake can be blocked by pretreatment with glucose analogues.Rossini et al. suggested that female CD-1 mice were less sensitive to the hyperglycemic effect of SZ than males. 20 ...