Structural and functional analysis of pancreatic islets preserved by pioglitazone in db/db mice.
To evaluate preventive effects of pioglitazone on pancreatic beta-cell damage in C57BL/KsJ db/db mice, an obese diabetic animal model, the pancreatic islets were compared morphologically between pioglitazone-treated (100 mg/kg daily po) and untreated db/db mice (n = 7 for each) after a 12-wk intervention (6-18 wk of age). The fasting blood glucose level was significantly improved by the treatment with pioglitazone (260 +/- 12 vs. 554 +/- 62 mg/dl, P < 0.05). The islet mass in the pancreas was significantly greater in pioglitazone-treated mice than in untreated mice (10.2 +/- 1.1 vs. 4.6 +/- 0.2 mg, P < 0.01). Subsequently, biochemical and physiological analyses of the beta-cell function were employed using pioglitazone-treated and untreated db/db mice (n = 6 for each) and pioglitazone-treated and untreated db/+ mice (n = 6 for each). After 2 wk of treatment (10-12 wk of age), the plasma levels of triglyceride and free fatty acid were significantly decreased, whereas the plasma adiponectin level increased significantly compared with the untreated group (65.2 +/- 18.0 vs. 18.3 +/- 1.3 microg/ml, P < 0.05). Pioglitazone significantly reduced the triglyceride content in the islets (43.3 +/- 3.6 vs. 65.6 +/- 7.6 ng/islet, P < 0.05) with improved glucose-stimulated insulin secretion. Pioglitazone showed no significant effects on the biochemical and physiological parameters in db/+ mice. The present study first demonstrated that pioglitazone prevents beta-cell damage in an early stage of the disease progression in db/db mice morphologically and physiologically. Our results suggest that pioglitazone improves glucolipotoxicity by increasing insulin sensitivity and reducing fat accumulation in the pancreatic islets.
Kawasaki
Fumiko
F
Diabetes and Endocrine Division, Dept. of Medicine, Kawasaki Medical School, 577 Matsushima, Kurashiki-shi, Okayama-ken 701-0192, Japan.
Matsuda
Masafumi
M
Kanda
Yukiko
Y
Inoue
Hiroshi
H
Kaku
Kohei
K
D052242:Adiponectin; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects / Q000235:genetics; D002452:Cell Count; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005947:Glucose / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D007328:Insulin / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D000078790:Insulin Secretion; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000077205:Pioglitazone; D011956:Receptors, Cell Surface / Q000235:genetics; D054411:Receptors, Leptin; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use; D014280:Triglycerides / Q000097:blood / Q000378:metabolism
D052242:Adiponectin; D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D045162:Thiazolidinediones; D014280:Triglycerides; D005947:Glucose; D000077205:Pioglitazone