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Diabetes 56:e17 2007
DOI: 10.2337/db07-0836
© 2007 by the American Diabetes Association
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Letter to the Editor

Response to Comment on: Marchand and Polychronakos (2007) Evaluation of Polymorphic Splicing in the Mechanism of the Association of the Insulin Gene with Diabetes: Diabetes 56:709–713

Luc Marchand, and Constantin Polychronakos

From the Endocrine Genetics Laboratory, McGill Health Center Research Institute, Montréal, Québec, Canada

Address correspondence to Constantin Polychronakos, MD, Endocrine Genetics Laboratory, McGill Health Center Research Institute, Montréal Children's Hospital, 2300 Tupper St. Ste. C244, H3H 1P3 Montréal, Québec, Canada. E-mail: constantin.polychronakos{at}mcgill.ca

Rodriguez et al. (1) are right in pointing out that our findings (2) do not rule out with absolute certainty a role for rs689 in type 1 diabetes through the effects on splicing under conditions not reflected in the tissues we examined. In biological science, absolute certainty is difficult to attain.

The mid-gestation fetal pancreata, subjected to a constant influx of nutrients and responding to an intensely anabolic state, is probably a good model for maximally upregulated insulin transcription. However, it is possible that the reduced ß-cell mass of type 1 pre-diabetes may represent a larger increase in transcription by individual cells, even against the inhibitory effect of cytokines in the context of insulitis. It is also possible that such increased transcription may alter the relative levels of splicing isoforms. What, in our opinion, is less plausible is that any increase in insulin production would have immunological effects in the microenvironment of the islet. T-cell receptors of infiltrating lymphocytes, regardless of avidity, are probably maximally saturated by the high local levels, and fast or slow splicing is unlikely to make a difference. In the thymus, where much lower concentrations are more likely to be within the saturation curve of T-cell receptor avidity, the splicing effect would result in higher levels of peptide derived from the predisposing allele. Such an effect would be in an opposite direction to that expected from the antigen-specific immune effects of thymic insulin expression levels that we (3) and others (4,5) have established in animal models of immune-mediated diabetes.

REFERENCES

  1. Rodriguez S, Gaunt TR, Vorechvsky I, Kralovicova J, Wood PJ, Day INM: Comment on: Marchand and Polychronakos (2007) Evaluation of polymorphic splicing in the mechanism of the association of the insulin gene with diabetes: Diabetes 56:709–713. Diabetes 56:e16, 2007. DOI: 10.2337/db07-0805[Free Full Text]
  2. Marchand L, Polychronakos C: Evaluation of polymorphic splicing in the mechanism of the association of the insulin gene with diabetes. Diabetes 56:709–713, 2007[Abstract/Free Full Text]
  3. Chentoufi AA, Polychronakos C: Insulin expression levels in the thymus modulate insulin-specific autoreactive T-cell tolerance: the mechanism by which the IDDM2 locus may predispose to diabetes. Diabetes 51:1383–1390, 2002[Abstract/Free Full Text]
  4. Thebault-Baumont K, Dubois-Laforgue D, Krief P, Briand JP, Halbout P, Vallon-Geoffroy K, Morin J, Laloux V, Lehuen A, Carel JC, Jami J, Muller S, Boitard C: Acceleration of type 1 diabetes mellitus in proinsulin 2-deficient NOD mice. J Clin Invest 11:851–857, 2003
  5. Faideau B, Lotton C, Lucas B, Tardivel I, Elliott JF, Boitard C, Carel JC: Tolerance to proinsulin-2 is due to radioresistant thymic cells. J Immunol 177:53–60, 2006[Abstract/Free Full Text]

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This Article
Right arrow Extract Freely available
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