title: Phlorizin treatment prevents the decrease in plasma insulin levels but not the progressive histopathological changes in the pancreatic islets during aging of Zucker diabetic fatty rats.
abstract: 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.
authors.affiliation: Department of Animal Physiology, Faculty of Science, University of Nijmegen, University Medical Centre Nijmegen, Nijmegen, The Netherlands.
authors.forename: S W J
authors.initials: SW
authors.lastname: Janssen
authors.forename: G J M
authors.initials: GJ
authors.lastname: Martens
authors.forename: C G J
authors.initials: CG
authors.lastname: Sweep
authors.forename: P N
authors.initials: PN
authors.lastname: Span
authors.forename: A A J
authors.initials: AA
authors.lastname: Verhofstad
authors.forename: A R M M
authors.initials: AR
authors.lastname: Hermus
mesh_terms: D000375:Aging; D000682:Amyloid / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight; D003920:Diabetes Mellitus / Q000097:blood* / Q000473:pathology*; D007328:Insulin / Q000097:blood* / Q000378:metabolism; D058228:Islet Amyloid Polypeptide; D007515:Islets of Langerhans / Q000473:pathology*; D008297:Male; D009004:Monosaccharide Transport Proteins / Q000037:antagonists & inhibitors; D009765:Obesity; D010695:Phlorhizin / Q000494:pharmacology*; D011506:Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker
chemical_list: D000682:Amyloid; D001786:Blood Glucose; D007328:Insulin; D058228:Islet Amyloid Polypeptide; D009004:Monosaccharide Transport Proteins; D011506:Proteins; D012333:RNA, Messenger; D010695:Phlorhizin