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Effect of prophylactic insulin treatment on the number of ER-MP23+ macrophages in the pancreas of NOD mice. Is the prevention of diabetes based on beta-cell rest?

Prophylactic insulin treatment has been shown to have beneficial effects in type 1 diabetes, both in humans and in various animal models of the disease. In experimental models, the protective effect of prophylactic 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 immunohistochemistry the effect of prophylactic insulin treatment vs placebo treatment (from 4 to 13 weeks of age) on ER-MP23+ macrophage infiltration in and around pancreatic islets in the non-obese diabetic (NOD) mouse, a spontaneous model for type 1 diabetes. BALB/c mice were used as diabetes-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 early infiltration of ER-MP23+ macrophages around islets, the reduction in severity of insulitis could already be detected as early as 9 weeks of age. With regard to the early accumulation of ER-MP23+ cells, we observed that their numbers per mm2 surface area of the exocrine pancreas and per micron at the circumference of the islet were higher in placebo-treated NODs (197 +/- 13.8 and 14 +/- 0.9, respectively) as compared to age-matched BALB/c mice (123.1 +/- 7.1 and 3.5 +/- 0.9, respectively). Prophylactic insulin treatment of NODs lowered the attraction of ER-MP23+ macrophages to the exocrine pancreas and to the circumference of the islets (156.3 +/- 8.5 and 7.9 +/- 1, respectively). Interestingly also, the islet size was found to be larger in placebo-treated NODs (51% was larger than 10 microns2) than in age-matched BALB/c mice (9% larger than 10 microns2). Prophylactic insulin treatment of NODs reduced their islet size to sizes found in the control BALB/c strain. In conclusion, the decrease in islet size by early insulin administration, and the lower attraction of ER-MP23+ macrophages to the islets are morphological indications that prevention of diabetes development by prophylactic insulin treatment results from a down-regulation of islet metabolism and growth, with a concomitant decline in the release of islet factors attracting macrophages.