Improvement of glucose tolerance in Zucker diabetic fatty rats by long-term treatment with the dipeptidyl peptidase inhibitor P32/98: comparison with and combination with rosiglitazone.
OBJECTIVE
The aim of this study was to investigate the effect of long-term treatment with the dipeptidyl peptidase inhibitor P32/98 and its combination with rosiglitazone on blood glucose control and islet of Langerhans histology in male Zucker diabetic fatty (ZDF) rats, when treatment begins before or after the development of overt diabetes.


METHODS
ZDF rats were treated with P32/98 from the age of 9, 12 or 15 weeks. Rosiglitazone maleate was given to a separate group from the age of 13 weeks. P32/98 was given to all of these rosiglitazone-treated rats from 16 weeks of age. Rosiglitazone maleate was also given from 16 weeks of age to half the rats that were given P32/98 from 9 weeks of age. The compounds were given by oral gavage until the rats were 14 weeks old and then in the diet. The experiment was terminated at the age of 20-21 weeks. Blood glucose, plasma insulin and oral glucose tolerance were measured at intervals; islet histology was assessed terminally.


RESULTS
P32/98 improved glucose tolerance after both single and multiple doses when treatment started at 9 weeks of age, also after the third week of treatment when treatment began at 12 or 15 weeks of age. P32/98 reduced daytime blood glucose when treatment began at 12 weeks. Treatment with rosiglitazone increased food intake and body weight, and after 2 weeks, reduced daytime blood glucose, water intake and the area under the glucose tolerance curve. A single dose of P32/98 markedly improved glucose tolerance in rosiglitazone-treated rats. When treatment had begun at 9 weeks of age, P32/98 stimulated insulin secretion in some glucose tolerance tests. Neither P32/98 nor rosiglitazone affected pancreatic insulin content, nor did they have clear effects on islet histology.


CONCLUSIONS
P32/98 elicited a sustained improvement in glucose tolerance in both prediabetic and diabetic ZDF rats. The effects of P32/98 on glucose and insulin were similar to those of rosiglitazone, and in contrast to rosiglitazone, P32/98 did not increase food intake or body weight. However, neither compound was especially effective at improving diabetes in ZDF rats when treatment began at 9, 12 or 15 (P32/98) or 13 (rosiglitazone) weeks of age.
Wargent
E
E
Clore Laboratory, University of Buckingham, Buckingham, UK.
Stocker
C
C
Augstein
P
P
Heinke
P
P
Meyer
A
A
Hoffmann
T
T
Subramanian
A
A
Sennitt
M V
MV
Demuth
H-U
HU
Arch
J R S
JR
Cawthorne
M A
MA
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects*; D001835:Body Weight; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D004326:Drinking; D004359:Drug Therapy, Combination; D004361:Drug Tolerance; D004435:Eating / Q000502:physiology; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood; D007515:Islets of Langerhans / Q000187:drug effects; D008297:Male; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism; D010421:Pentanoic Acids / Q000097:blood / Q000627:therapeutic use*; D051381:Rats; D011924:Rats, Zucker; D000077154:Rosiglitazone; D013844:Thiazoles / Q000097:blood / Q000627:therapeutic use*; D045162:Thiazolidinediones / Q000627:therapeutic use*; D053778:Thiazolidines; D013997:Time Factors
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; C453900:P32-98 compound; D010421:Pentanoic Acids; D013844:Thiazoles; D045162:Thiazolidinediones; D053778:Thiazolidines; D000077154:Rosiglitazone; D018819:Dipeptidyl Peptidase 4