Immunoreactive insulin (IRI) concentrations were measured in plasma and cerebrospinal fluid (CSF) of four-month old genetically obese Zucker rats, their heterozygote lean littermates, and age-matched normal-weight Wistar rats. Basal plasma IRI was 201 + 35 microU/ml (means +/- SEM) in the obese animals and was significantly elevated compared to both lean Zucker rats (18 +/- 2.4 microU/ml, P less than 0.001) and Wistar rats (12 +/- 2.4 microU/ml, P less than 0.001). The mean CSF IRI concentration of fasted obese Zucker rats was 1.59 +/- 0.19 microU/ml; this was significantly higher than the CSF IRI level of either fasted Zucker lean rats (0.31 +/- 0.08 microU/ml, P less than 0.001) or Wistar rats (0.34 +/- 0.12 microU/ml, P less than 0.001). Plasma and CSF IRI concentrations were increased in free-feeding as compared with fasted animals. These data provide evidence that endogenous CSF insulin is derived from circulating plasma insulin in the rat and suggest that the hyperphagia and obesity of the Zucker fatty rat are not due to an inability of circulating insulin to gain access to the CSF.

Dear Sir, We noted with interest the recent Short communication by O. Rolandsson et al. [1] which assessed autoantibodies to the 65 kD glutamate decarboxylase isoform and to the tyrosine phosphatase-like proteins in a Scandinavian population and found an association with IGT. These autoantibodies have previously been measured in recent-onset adult diabetes patients who had clinical Type II (non-insulin-dependent) diabetes mellitus but develop the need for insulin treatment within 2 years, suggesting late-onset Type I (insulin-dependent) diabetes mellitus. The finding of an association of the same autoantibodies with IGT could be explained by the possible early diagnosis of an even milder form of Type I diabetes. In this new report, the authors made the surprising observation that obesity as assessed by BMI was also associated with these autoantibodies. The mechanism for this association was not further discussed. Assuming that these autoantibodies indicate prior beta-cell immune damage [2] followed by impaired beta-cell function in this population, we would like to suggest as postulated in our recent review [3] that these findings can be explained by the effect of reduced insulin secretion to increase food intake by reducing the suppressive effect of insulin on the CNS. This is due to insulin's ability to suppress, critical hypothalamic hyperphagic food intake regulatory neuropeptides, particularly neuropeptide-g. The subsequent increase in food intake in turn would increase pancreatic demand for insulin secretion due to the increased fat mass and its associated decrease in insulin sensitivity. In this way, IGT would be more likely to develop and eventually increase the risk of clinical diabetes which would be aetiologically a form of late-onset or mild Type I diabetes presenting with the clinical features of Type II diabetes. Thus, we postulate that the CNS could be the critical factor in the association between islet cell autoantibodies and BMI. This was also suggested in our review [4] of the development of Type II diabetes in Japanese-Americans. In these subjects an association between beta-cell dysfunction and a promoter variant in the glucokinase gene [5] was observed which could explain the sequence of beta-cell impairment followed by intra-abdominal obesity leading to Type II diabetes as described previously [6]. Thus, we suggest that the effects of insulin deficiency on the CNS could explain both the antibody findings in Scandinavians developing obesity and IGT [1] and the development of classical Type II diabetes in Japanese-Americans.Yours sincerely,