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

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reduced beta-cell mass can lead to impaired function but the mechanism is not yet apparent
nor is it necessarily the sole factor (21).
Two possible explanations account for the impaired beta-cell function consequent to
decreased beta-cell mass (21): 1. Increased insulin demand on residual beta cells per se
leading to changes in function (by ER-stress or other mechanisms); 2. Hyperglycemia
consequent to decreased beta-cell mass driving the impairement in beta-cell function.
However, the decreasing beta-cell mass experimentally more often than not leads to a more
or less prolonged period of hyperglycemia (79, 80). Moreover, in many instances there is
compensatory regeneration of beta cells which might not be as well-differentiated as older,
fully mature cells. Regardless, there are in vitro studies on islet and in vivo studies by
glucose infusion showing that high glucose for prolonged periods of time lead to impaired
beta-cell mass and/or function. Therefore, accepting that glucose plays a central role among
those factors contributing to beta-cell demise while transient postprandial hyperglycemic
excursions may predominantly induce beta-cell proliferation in insulin-resistant individuals,
this adaptive mechanism may fail in the long term and be overridden by beta-cell apoptosis.
However, it is unlikely that glucotoxicity acts alone, and the negative contribution of
saturated fatty acids, lipoproteins, leptin and circulating and locally produced cytokines will
further burn out the beta-cells. These factors will induce apoptosis and/or necrosis, which in
the presence of pro-inflammatory cytokines may activate specific immunological
phenomena ultimately resulting in autoimmunity as indicated above (46).
Notwithstanding, DM 2 in humans progresses over time, while impaired beta-cell
function appears to be reversible at least to a certain degree in the early stages of the
disease. In effect, the overnight infusion of glucagon-like peptide 1(GLP-1) in DM2
improved first and second phase insulin responses to a 2-hour hyperglycemic clamp. All
responses on GLP-1 were not significantly different from non-diabetic control subjects
(81). Besides, a recovery of the first-phase insulin secretion was observed after the addition
of rosiglitazone given for 6 months to failing sulfonylurea and metformin regimen in DM2
with a duration of diabetes of 7.6 ± 2.1 years (82). Similarly, the intravenous administration
of the incretin mimetic, exenatide, maintained for 30 minutes, to DM2 patients treated with
diet/exercise, with a duration of the disease of 4 ± 2 years, restored the first and second
phases of insulin secretion, after glucose challenge, with a pattern similar to that found in