A B S T R A C T The relationship between the dose of intravenously administered streptozotocin (a N-nitroso derivative of glucosamine) and the diabetogenic response has been explored by use of the following indices of diabetogenic action: serum glucose, urine volume, and glycosuria, ketonuria, serum immunoreactive insulin (IRI), and pancreatic IRI content. Diabetogenic activity could be demonstrated between the doses of 25 and 100 mg/kg, all indices used showing some degree of correlation with the dose administered. Ketonuria was only seen with the largest dose, 100 mg/kg. The most striking and precise correlation was that between the dose and the pancreatic IRI content 24 hr after administration of the drug, and it is suggested that this represents a convenient test system either for both related and unrelated beta cytotoxic compounds or for screening for modifying agents or antidiabetic substances of a novel type. Ability to produce graded depletion of pancreatic IRI storage capacity led to an analysis of the relationship between pancreatic IRI content and deranged carbohydrate metabolism. Abnormal glucose tolerance and insulin response were seen when pancreatic IRI was depleted by about one-third, while fasting hyperglycemia and gross glycosuria occurred when the depletion had reached twothirds and three-quarters, respectively. The mild yet persistent anomaly produced by the lowest effective streptozotocin dose, 25 mg/kg, exhibits characteristics resembling the state of chemical diabetes in humans and might thus warrant further study as a possible model. Finally, the loss of the diabetogenic action of streptozotocin by pretreatment with nicotinamide was confirmed and was shown to be a function of the relative doses of nicotinamide and streptozotocin and of the interval between injections.

The metabolic effects of recombinant human insulin-like growth factor-I (IGF-I) were assessed in five groups of normal male overnight-fasted volunteers receiving infusions of either 0, 5, 7.5, 15, or 30 micrograms/kg.h IGF-I during 8 h, resulting in total plasma IGF-I concentrations 127 +/- 7, 247 +/- 30, 389 +/- 39, 573 +/- 62, 620 +/- 105 ng/ml, respectively. Glucose consumption (euglycemic glucose clamp) increased dose dependently during IGF-I infusion (P < 0.001) up to 6.7 +/- 1.3 mg/kg. min in the 30 micrograms/kg.h group. Plasma triglyceride concentrations decreased with increasing doses of IGF-I (P < 0.03); the fall was 43% in the 30 micrograms/kg.h group. Plasma free fatty acid concentrations decreased during 7.5, 15, and 30 micrograms/kg.h IGF-I by 23%, 34%, and 48%, respectively. IGF-I lowered plasma beta-hydroxybutyrate concentrations in a dose-dependent manner (P < 0.025). Plasma concentrations of leucine and alpha-ketoisocaproate decreased dose dependently (P < 0.001 and P < 0.015). Whole body leucine flux (1-13C-leucine infusion technique) decreased with increasing doses of IGF-I by 41% during 30 micrograms/kg.h, indicating decreased whole body protein breakdown. Leucine oxidation into 13CO2 decreased with increasing doses of IGF-I (P < 0.045) by 57% in the 30 micrograms/kg.h group, suggesting inhibition of irreversible loss of leucine. Plasma C-peptide and insulin concentrations decreased dose dependently (P < 0.005 and P < 0.02), indicating diminished insulin secretion. Thus, acute elevation of plasma IGF-I concentrations in man results in metabolic effects which are qualitatively similar to those described previously of insulin.

Spiny mice (Acomys) are a group of small rodents indigenous to the Eastern Mediterranean and Africa. The Acomys Cahirinus strain reported on here is indigenous to Israel. The strain is characterized by striking and congenital hyperplasia of the islets of Langerhans, primarily of the beta cells. The endocrine tissue contributes up to 15 per cent of the pancreatic mass in adults, up to 25 per cent in the newborn. Pancreatic insulin content may be as high as 100 units per gram wet weight. When fedad libitum in the laboratory approximately one-half of the animals become obese, while approximately 15 per cent develop a diabetes mellitus-like state with moderate hyperglycemia, glucosuria, and, less frequently, ketonuria accompanied by weight loss and, ultimately, death. The development of the diabetic state is associated with degranulation and, later, striking glycogenic degeneration of the beta cells of the islets of Langerhans. There is also severe glycogenic nephrosis and myocardosis and preliminary observations suggest the presence of thickening of the capillary basement membrane of the renal glomeruli and in the endocrine pancreas. The interrelationships of hyperplasia of the islets of Langerhans, obesity, and diabetes mellitus are as yet to be established, as are the genetic characteristics of each of these entities. An important area of potential usefulness derives from the degree of the hyperplasia of the endocrine tissue, since this should greatly facilitate ultrastructural studies, microdissection and transplantation, as well as organ or tissue culture work. Also, the association of anomalies observed in these spiny mice may, through their systematic study, provide clues for the study of the association of diabetes and obesity with relative hyperinsulinism in man.

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