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

39
with significant improvement in AIR g and increased disposition index (AIR g x 1/HOMA-
IR), the restoration of the first-phase insulin response to glucose being independent of the
correction of glucose toxicity. Clinical studies using rosi- or pioglitazone have
demonstrated a beneficial effect of both agents in improving insulin sensitivity and
recovery or improvement of beta-cell function which are sustained in some individuals over
time. The addition of rosiglitazone improved the first-phase insulin response to glucose in
poorly controlled patients previously treated with maximum doses of
sulfonylurea+metformin. However, the addition of insulin had no effect on beta-cell
function, despite a similar reduction in HbA1c.
The several trials on prevention of diabetes with TZDs include the following:
Troglitazone and Pioglitazone on Prevention of Diabetes (TRIPOD and PIPOD), in
which troglitazone (withdrawn in 2000, because of hepatotoxicity) and subsequently
pioglitazone delayed or prevented the onset of diabetes. The class effect of TZDs on
reducing insulin secretory demands (decrease in insulin output during FSIVGTT) through a
decrease in insulin resistance preserved beta-cell function and prevented DM2. The
Diabetes Prevention Program (DPP) was a clinical trial of DM2 prevention, from 1996 to
1998, in individuals at high risk of diabetes, involving adults with IGT, who were
randomized to placebo, metformin, troglitazone or intensive lifestyle intervention.The
diabetes incidence rate was 3.0 cases/100 person-years in troglitazone group (mean of 0.9
years), compared with 12.0, 6.7 and 5.1 cases /100 person-years in placebo, metformin and
intensive lifestyle participants. The trial of TZD therapy in the prevention/delay of DM2
in patients with IFG+ IGT, in which 101 subjects received troglitazone for an average of
10 months (at which point the drug was withdrawn) then randomly switched to
rosiglitazone or pioglitazone for a mean of 36 months. The cumulative incidence rate of
diabetes after the 3 years was 2.97% after TZDs vs.26.8% in the control group: IFG+ IGT
(p