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

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healthy paired controls (83). These results are compatible with the view that the deficient
pattern of insulin secretion is mainly functional in nature and that the reduction in
pancreatic islet mass is moderate in patients with DM2 (4, 83). However, the recovery of
insulin secretion should be tested in further studies focusing on patients with more
advanced stages of DM2. Furthermore, if an individual with DM2, even with severe
hyperglycemia, is rendered euglycemic by either pharmacological means or changes in life-
style, beta-cell function, in particular glucose-reponsiveness can be restored, will be
discussed later. This is particularly true in newly diagnosed DM2 (84, 85) where the
limiting threshold for reversibility of decreased beta-cell mass has probably not been
passed. Rendering an individual with DM2 euglycemic interrupts the vicious circle linking
decreased beta-cell function with hyperglycemia. This might not only restore insulin
secretory patterns but also allow for some restoration of beta-cell mass. Although there are
many reasons to believe that this may occur in humans as it does in animal models of
reduced beta-cell mass, this has never been documented by virtue of the fact that beta-cell
mass cannot be measured non-invasively at the time of writing.
Understanding the mechanisms of beta-cell death and thus the decreased beta-cell
mass and impaired function has provided the basis for a new therapeutic target, beta-cell
preservation, particularly when one considers the reversibility of impaired beta-cell
function and possibly beta-cell mass as discussed above. In this context, it should be noted
that long-acting incretin mimetics, which besides enhancing glucose-sensing and insulin
secretory capacity of the endocrine pancreas have also been shown in preclinical studies in
rodents, to have additional effects on beta-cell mass by stimulating proliferation and
inhibiting apoptosis (86).
Other examples include the thiaozolidinediones (TZDs) which have been linked to
not only improving insulin secretory capacity but also preventing the loss of beta-cell mass
by reducing apoptosis with maintenance of beta-cell neogenesis in ZDF rats (87) as well as
in other murine models of type 2 diabetes (88). In human beings, TZDs were able to
preserve and recover beta-cell function (82, 89) besides improving insulin sensitivity.
Summary / Conclusions