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An. R. Acad. Nac. Farm., 2007, 73: 763-784

Sesiones

From Pathogenesis to Therapeutic of Type 2
Diabetes. The GK Rat Paradigm

Recibido el 19 de abril de 2007

BERNARD PORTHA *
Lab. Physiopathologie de la Nutrition, CNRS UMR 7059,

Equipe B2PE
Université Paris-Diderot/UP7, 2 Place Jussieu,

75251 Paris Cedex 05, France

ABSTRACT

Now that the reduction in beta-mass has been clearly established in humans
with type 2 diabetes mellitus (T2D), the debate focuses on the possible mechanisms
responsible for abnormal islet microenvironment, decreased beta-cell number and
impaired beta-cell function, and their multifactorial aetiologies. The informations
available in the Goto-Kakizaki (GK/Par line) rat, one of the best characterized
animal models of spontaneous T2D, are reviewed in such a perspective. We propose
that the defective beta-cell mass and function in the GK/Par model reflects the
complex interactions of three pathogenic players: i) several independent loci
containing genes responsible for some diabetic traits (but not decreased beta-cell
mass); (ii) gestational metabolic impairment inducing a programming of endocrine
pancreas (decreased beta-cell neogenesis) which is transmitted to the next
generation; and (iii) secondary (acquired) loss of beta-cell differentiation due to
chronic exposure to hyperglycaemia (glucotoxicity). An important message is that
the «heritable» determinants of T2D do not simply rely on genetic factors, but

* Discurso de Toma de Posesión de Académico Correspondiente.
Address correspondence to:
Prof. B. Portha
Lab. Physiopathologie de la Nutrition, CNRS UMR 7059, Université Paris-Diderot,
2 place Jussieu, Tour 33.
75251 Paris Cedex 05, France.
Telephone: +33 144 27 50 11. Fax: +33 144 27 78 91
mail: portha@univ-paris-diderot.frD

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