Elsevier

The Lancet

Volume 293, Issue 7594, 15 March 1969, Pages 554-558
The Lancet

Hypothesis
EARLY-ONSET DIABETES MELLITUS IN THE GENERAL AND DOWN'S SYNDROME POPULATIONS: Genetics, Ætiology, and Pathogenesis

https://doi.org/10.1016/S0140-6736(69)91961-8Get rights and content

Abstract

A comparison of the age-distribution of early-onset diabetes mellitus in a general population in Sweden, with that in a Down's syndrome population in the United States shows that peak initiationrates occur at 14 years of age in the general population, but at about 8 years of age in the Down's syndrome population. From the detailed form of the age-patterns, and a general biological theory, it is suggested that the disease process is initiated in a genetically predisposed person by two random somatic mutations in a single growth-control stem cell. These somatic mutations probably affect homologous genes at a locus on chromosome 21. The mutant stem cell propagates a " forbidden clone " of descendant cells, and the secreted humoral products of these cells attack target cells—most likely beta cells in the islets of Langerhans. For disorders of this general class the term " autoaggressive", is suggested. (Autoaggressive disorders include the so-called idiopathic " autoimmune " diseases.) Genetic predisposition to early-onset diabetes mellitus is polygenic-probably pa1/pa1, pb/pb1, together with an X-linked factor with recessive expression. The autosomal allele pb1 may well be located on chromosome 21. Predisposition to lateonset diabetes involves the autosomal alleles pa1/pa1 and an X-linked factor, with recessive expression in some populations, and dominant in others. Independent familial, anatomical, and serological evidence supports this hypothesis.

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