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

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