A hallmark of
Type 2 diabetes mellitus (T2DM) is chronic
hyperglycemia, which is thought to play a role in pancreatic beta-cell failure. Here we investigated whether treatment of Zucker diabetic fatty (ZDF) rats, an animal model for T2DM, with the renal
glucose transport inhibitor
phlorizin could prevent alterations in the pancreatic islets. ZDF rats were treated with
phlorizin or vehicle for 13 weeks starting with 6-week-old rats and before the onset of
hyperglycemia. During the treatment,
blood glucose levels in
sham-treated ZDF rats increased rapidly from 7.7 +/- 0.3 to 24.8 +/- 0.6 mmol/l, whereas those in
phlorizin-treated ZDF rats increased only slightly, but significantly, from 7.0 +/- 0.2 to 8.9 +/- 0.6 mmol/l.
Phlorizin prevented the decrease in plasma
insulin levels and caused a higher increase in
body weight of the ZDF rats. Compared to 6-week-old untreated ZDF rats, in 19-week-old
sham- and
phlorizin-treated ZDF rats similar changes were found in islet architecture (more irregular boundaries and a disrupted mantle of peripheral islet cells) and in the mitochondria at the ultrastructural level (swelling of the matrix and disruption of the cristae). Using
reverse transcriptase-polymerase chain reaction, no differences in
mRNA expression levels were found for
insulin,
islet amyloid polypeptide (IAPP), and the
prohormone convertase (PC) 1 and PC2 between 6-week-old untreated ZDF rats and 19-week-old
sham- and
phlorizin-treated ZDF rats. However, immunohistochemistry revealed similar decreases in
insulin and
IAPP protein expression in 19-week-old
sham- and
phlorizin-treated ZDF rats compared to those in 6-week-old untreated ZDF rats. These observations indicate that during aging of ZDF rats
phlorizin treatment does not prevent the decreases in
insulin and
IAPP protein expression and the progressive histopathological changes in the pancreatic islets. Therefore, it is highly unlikely that these changes are caused by chronic
hyperglycemia.