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

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(130, 131, 132, 133, 134, 89). Further evidence that TZDs exerts beneficial effects on beta-
cell derive from a study in which 2 months`treatment with pioglitazone restored the first-
phase insulin response to an intravenous glucose tolerance test, in both patients with IGT
and with frank type 2 diabetes (135). Similar results were reported in a randomized 6-
month study comparing the addition of rosiglitazone versus insulin in patients with type 2
diabetes who were inadequately controlled on glimepiride and metformin ,using a
frequently sampled intravenous glucose tolerance test (82). At study end,the acute insulin
response to glucose was significantly increased with rosiglitazone, with no effect of
exogenous insulin apparent. Beta-cell function determined by the disposition index,
calculated as the product of acute insulin response to glucose and the insulin sensitivity
index (Si = 1/HOMA-IR) also increased greatly. It should be noted that the restoration of
the first-phase insulin response to glucose was independent of the correction of glucose
toxicity.
Furthermore, extension studies with TZDs indicate that improvements in beta-cell
function are sustained in some individuals over time. Four 52-week clinical trials, involving
over 3,700 patients with type 2 diabetes, reviewed by Campbell (136), showed that
pioglitazone was an effective long-term treatment, both as monotherapy and in combination
with metformin or sulfonylurea. As well as maintaining glycemic control over the long-
term, pioglitazone also yielded benefits in terms of improvements in fasting insulin (which
was reduced as proinsulin and C-peptide), lipid parameters and hypoglycemia compared
with other monotherapies or combination treatments. The longest follow-up study was that
by Bell and Ovalle (137, 138), of type 2 diabetics on sulfonylurea, metformin and
rosiglitazone for 60 months, in which 22 of the patients (68%) put on the triple therapy
remained relatively well controlled. The predictor of failure and the use of insulin was
necessary after a mean duration of 30 months was the non-significant or lack of increase in
the meal or glucagon stimulated C-peptide. At 60 months, a frequent finding was also a
reduction in fasting C-peptide in the failure group.
TZDs may also improve insulin processing, as demonstrated by a reduction in the
proinsulin to total immunoreactive insulin ratio(PI/IRI), an important indicator of beta-cell
dysfunction outlined earlier (23). Rosiglitazone produced a decrease in the PI/IRI ratio in