Interleukin-1 effect on glycemia in the non-obese diabetic mouse at the pre-diabetic stage

Abstract

Cytokines, particularly interleukin 1 (IL-1) and tumor necrosis factor, are known to induce hypoglycemia in normal rodents or different experimental models of type II diabetes. We investigated, at the pre-diabetic stage, the effect of short-term administration of murine recombinant interleukin-1 alpha (mrIL-1 alpha) on the levels of glucose, insulin and corticosterone in the non-obese diabetic (NOD) mouse, a spontaneous model of type I diabetes. Two-month-old, pre-diabetic NOD mice of both sexes were insensitive to mrIL-1 alpha (12.5 and 50 micrograms/kg) 2 h after administration, the time at which the maximal decrease (around 50%) was observed in the C57BL/6 mouse strain. Kinetic studies however showed that mrIL-1 alpha lowered glycemia in both sexes of NOD mice, but the effect was limited and delayed. In the NOD and C57BL/6 strains, mrIL-1 alpha had no influence on insulin levels in females, but significantly increased them in males (P < 0.0001). Castration of NOD males abrogated the stimulatory effect of mrIL-1 alpha on insulin secretion. Corticosterone secretion was stimulated by mrIL-1 alpha in both sexes of NOD and C57BL/6 mice, and this effect was faster and greater in NOD females than in C57BL/6 females. The incomplete hypoglycemic response to mrIL-1 alpha in females may be attributed to the anti-insulin effect of glucocorticoids, an effect which can be demonstrated when mrIL-1 alpha is administered to adrenalectomized animals or when mrIL-1 alpha is administered together with the glucocorticoid antagonist RU38486. In NOD males, in contrast, glucocorticoids did not play a major role in the limited hypoglycemic response to mrIL-1 alpha, since RU38486 and adrenalectomy were not able to unmask a hypoglycemic effect. Moreover, NOD mice of both sexes were less sensitive than C57BL/6 mice to the hypoglycemic effect of insulin (2.5 U/kg), which suggests some degree of insulin-resistance in NOD mice. With regard to the effect of IL-1 on NOD mouse glycemia, therefore, these results suggest that glucocorticoids and/or androgens, according to the animal's sex, may induce a state of insulin-resistance.

Contribution of Different Mechanisms to Pancreatic Beta-cell Hyper-secretion in Non-obese Diabetic (NOD) Mice during Pre-diabetes

“…Blood glucose levels 20 -60 min after intravenous glucose infusions were significantly lower in 6-week-old NOD mice compared with the control (Fig. 1A), which suggested an excessive insulin release, as has been previously proposed (3,26). The Ca 2ϩ clearance and glucosestimulated calcium oscillations of individual NOD beta-cells were not significantly different from those of Balb/c cells (Figs.…”

Nonobese diabetic mice express aspects of both type 1 and type 2 diabetes

“…However, in those experiments 2-month-old mice were analyzed, and at this age the islets of NOD mice are already fully infiltrated by lymplocytes. It was suggested that the production of inflammatory cytokines such as IL-1 in the insulitic islets is a crucial contributing factor to the insulin resistance (15).…”

Resistance of T-cells to apoptosis in autoimmune diabetic (NOD) mice is increased early in life and is associated with dysregulated expression of Bcl-x

“…In this regard, in two other models of autoimmunity, the diabetic BB rat and the Obese chicken, a model of Hashimoto's thyroiditis, an altered affinity of corticosteroid-binding globulin (CBG) caused by a point mutation and an elevated level of CBG, respectively, were reported [27,28]. Likewise, NOD mice develop an abnormal corticosterone response to a stimulation by IL-1a [29]. Such alterations of the immune endocrine system could influence autoimmune susceptibility by modulating sensitivity of autoreactive clones to apoptosis independently of their intrinsic resistance to PCD.…”