1 BETA-CELL FAILURE IN DIABETES AND PRESERVATION BY ...

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Numbering among the factors for progressive loss of beta-cell function and mass,
are glucotoxicity and lipotoxicity, which are closely interrelated in the sense that
lipotoxicity does not exist without chronic hyperglycemia and depending on duration of
exposure to glucose or FFAd and on genetic background of the islets, may induce beta-cell
proliferation and have pro- or anti-apoptotic effects
Pro-inflammatory cytokines and leptin, produced by fat tissue, could also affect
beta-cells. In particular, leptin, TNF-α, IL-6 and IL-1 receptor antagonist are a linkage of
obesity to DM2.Leptin in islets leads to beta-cell apoptosis, while TNF-α and IL-6 may
also modulate beta-cell survival. Apoptotic cells can provoke mobilization of T cells
reactive to beta-cell antigens, culminating in autoimmune destruction of beta-cells similar
to that observed at earlier stages of type l diabetes.
Regarding the IAPP, several evidences support its role in the pathophysiology of
beta-cells loss in DM2. Alternatively, it is possible that IAPP formation is secondary to the
onset of hyperglycemia and not of primary importance in the pathophysiology of DM2.
The link of reduced beta cell mass to impaired function, may be due to an increased
demand on residual beta cells per se leading to changes in function(ER-stress or other
mechanisms) or related to the hyperglycemia consequent to decreased beta-cell mass,
driving the impairement in beta-cell function. In vitro and in vivo studies suggested that
persistenly elevated glucose levels play a central role among those factors (FFAs,
lipoproteins, leptin and cytokines) contributing to beta-cell demise.
Understanding the mechanisms of beta-cell death and thus decreased beta-cell mass
and impaired function has provided the basis to beta cell preservation, particularly when
one considers that the impaired beta-cell function and possibly beta-cell mass appears to be
reversible particularly at early stages of the disease where the limiting threshold for
reversibility of decreased beta-cell mass has probably not been passed.
IV. Clinical intervention to preserve or “rejuvenate” beta-cells
A. Short-term intensive insulin therapy of newly diagnosed DM2