EFFECT OF PROPHYLACTIC INSULIN-TREATMENT ON THE NUMBER OF ER-MP23(- IS THE PREVENTION OF DIABETES BASED ON BETA-CELL REST() MACROPHAGES IN THE PANCREAS OF NOD MICE )

Prophylactic insulin treatment has been shown to have beneficial effec ts in type 1 diabetes, both in humans and in various animal models of the disease. In experimental models, the protective effect of prophyla ctic insulin treatment was observed in two parameters: (1) progression of insulitis and (2) diabetes incidence. The mechanism of protection still remains to be investigated. We therefore analysed by immunohisto chemistry the effect of prophylactic insulin treatment vs placebo trea tment (from 4 to 13 weeks of age) on ER-MP23(+) macrophage infiltratio n in and around pancreatic islets in the non-obese diabetic (NOD) mous e, a spontaneous model for type 1 diabetes. BALB/c mice were used as d iabetes-free controls. Using conventional haematoxylin-eosin staining, we detected a protective effect of prophylactic insulin treatment in NOD females on the lymphocytic insulitis, significant at 13 weeks, but not at 9 weeks of age. However, when assessed by immunostaining for e arly infiltration of ER-MP23(+) macrophages around islets, the reducti on in severity of insulitis could already be detected as early as 9 we eks of age. With regard to the early accumulation of ER-MP23(+) cells, we observed that their numbers per mm(2) surface area of the exocrine pancreas and per mu m at the circumference of the islet were higher i n placebo-treated NODs (197+/-13.8 and 14+/-0.9, respectively) as comp ared to age-matched BALB/c mice (123.1+/-7.1 and 3.5+/-0.9, respective ly). Prophylactic insulin treatment of NODs lowered the attraction of ER-MP23(+) macrophages to the exocrine pancreas and to the circumferen ce of the islets (156.3+/-8.5 and 7.9+/-1, respectively). Interestingl y also, the islet size was found to be larger in placebo-treated NODs (51% was larger than 10 mu m(2)) than in age-matched BALB/c mice (9% l arger than 10 mu m(2)). Prophylactic insulin treatment of NODs reduced their islet size to sizes found in the control BALB/c strain. In conc lusion the decrease in islet size by early insulin administration, and the lower attraction of ER-MP23(+) macrophages to the islets are morp hological indications that prevention of diabetes development by proph ylactic insulin treatment results from a downregulation of islet metab olism and growth, with a concomitant decline in the release of islet f actors attracting macrophages. (C) 1996 Academic Press Limited