title: Effect of sitagliptin plus metformin on β-cell function, islet integrity and islet gene expression in Zucker diabetic fatty rats.
abstract: OBJECTIVE
  The combination of metformin and a dipeptidyl peptidase 4 (DPP-4) inhibitor has been shown to be an effective, safe, and well-tolerated treatment for type 2 diabetes. We evaluated β-cell function and morphological changes in islets in Zucker diabetic fatty (ZDF) rats following combined therapy with sitagliptin and metformin and investigated the expression of potentially relevant genes using cDNA microarrays.
  
  
  METHODS
  Nine-week-old ZDF rats were randomly divided into four treatment groups: no treatment (control); sitagliptin; metformin, and sitagliptin plus metformin. After 5 weeks of treatment, an oral glucose tolerance test was performed and plasma levels of active GLP-1 and islet morphology and gene expression were assessed.
  
  
  RESULTS
  Combination therapy reduced fasting glucose and postprandial plasma glucose levels and increased active GLP-1 levels, compared with monotherapy. Combination therapy also increased insulin secretion, the proportion of small islets, and the intensity of insulin staining. Furthermore, it increased the expression of genes involved in cell survival and growth and downregulated apoptosis-associated genes, relative to monotherapy.
  
  
  CONCLUSIONS
  Combination treatment with sitagliptin and metformin preserved β-cell function and β-cell integrity in ZDF rats. This may be associated with the transcriptional activation of anti-apoptotic and pro-survival genes, as well as the suppression of pro-apoptotic genes.
authors.affiliation: Department of Endocrinology and Metabolism, Ajou University School of Medicine, San 5, Wonchon-dong, Yeongtong-gu, Suwon, Gyeonggi-do, Republic of Korea.
authors.forename: Seung Jin
authors.initials: SJ
authors.lastname: Han
authors.forename: Sung-E
authors.initials: SE
authors.lastname: Choi
authors.forename: Yup
authors.initials: Y
authors.lastname: Kang
authors.forename: Jong Gab
authors.initials: JG
authors.lastname: Jung
authors.forename: Sang-A
authors.initials: SA
authors.lastname: Yi
authors.forename: Hae Jin
authors.initials: HJ
authors.lastname: Kim
authors.forename: Kwan Woo
authors.initials: KW
authors.lastname: Lee
authors.forename: Dae Jung
authors.initials: DJ
authors.lastname: Kim
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D011719:Pyrazines / Q000494:pharmacology*; D051381:Rats; D011924:Rats, Zucker; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000494:pharmacology*; D050807:ets-Domain Protein Elk-1 / Q000378:metabolism
chemical_list: D007004:Hypoglycemic Agents; D011719:Pyrazines; D014230:Triazoles; D050807:ets-Domain Protein Elk-1; D052216:Glucagon-Like Peptide 1; D008687:Metformin; D017526:Receptor, IGF Type 1; D053148:Caspase 3; D000068900:Sitagliptin Phosphate