Interleukin-1-beta, tumor necrosis factor-alpha, insulin secretion and oral glucose tolerance in non-diabetic siblings of children with IDDM

Abstract

Recent reports suggest that the pancreas participates in tumor necrosis factor alpha (TNF-A) production during stress, and that the islets are predominantly responsible for such synthesis. In vitro TNF-A and interleukin 1-beta (IL-1-beta) inhibit insulin release from islet beta-cells. We measured the circulating levels of IL-1-beta, TNF-A and islet cell antibody (ICA) in 30 children with IDDM (10 of them at their first presentation), 30 of their non-diabetic siblings, and 30 normal age-matched children. In the non-diabetic children we investigated the early phase of insulin release after intravenous bolus of glucose and evaluated tolerance to oral glucose (OGTT). IL-1-beta and TNF-A concentrations were significantly higher in IDDM-siblings (31.8 +/- 7.7 pg/ml and 650 +/- 155 pg/ml respectively) versus normal children (21.2 +/- 6.4 pg/ml and 383 +/- 122 pg/ml respectively). IL-1-beta and TNF-A concentrations did not differ significantly between the diabetic children and healthy age-matched controls. ICA were detected in 60% of the recently diagnosed diabetic children vs. 30% of those with longer duration of diabetes (3.1 +/- 1.2 years). Despite the significantly high prevalence of ICA in the recently diagnosed children with IDDM, their IL-1-beta and TNF-A concentrations were lower than those for the normal children. In experimental animals these cytokines can induce round cell infiltration (insulinitis) and inhibit insulin secretion by beta-cell. The presence of significantly higher concentrations of these cytokines in IDDM siblings, with high prevalence of ICA (16%), was associated with normal oral glucose tolerance and normal peak insulin response (60 +/- 10.4 mlU/ml) after i.v. glucose bolus compared to normal children (52.3 +/- 9.5 mlU/ml). However, after 2 years of follow up, one of them developed IDDM and another developed IGT but none of the normal controls developed abnormal glucose tolerance. It appears that the process of autoimmune aggression against beta-cells, and its effect on insulin release and glucose homeostasis, is a slow and chronic process. However, the production of these cytokines and consequently the degree of beta-cell destruction, in a genetically susceptible subject, might be enhanced by several factors including viral infections. In summary, IL-1-beta and TNF-A levels can be used as indicators of continuing autoimmune aggression against beta-cells before the development of extensive beta-cell destruction.