Defective functional β-cell mass and Type 2 diabetes in the Goto-Kakizaki rat model

Increasing evidence indicates that decreased functional β-cell mass is the hallmark of Type 2 diabetes mellitus. Therefore, the debate focuses on the possible mechanisms responsible for abnormal islet microenvironment, decreased β-cell number, impaired β-cell function and their multifactorial etiologies. The information available on the Goto-Kakizaki/Par rat line, one of the best characterized animal models of spontaneous Type 2 diabetes mellitus, are reviewed in such a perspective. We propose that the defective β-cell mass and function in the Goto-Kakizaki/Par model reflect the complex interactions of multiple pathogenic players, including several independent loci containing genes responsible for some diabetic traits (but not decreased β-cell mass), gestational metabolic impairment inducing an epigenetic programming of the pancreas (decreased β-cell neogenesis), which is transmitted to the next generation, and loss of β-cell differentiation due to chronic exposure to hyperglycemia, inflammatory mediators, oxidative stress and perturbed islet microarchitecture.