title: Gene expression regulated by pioglitazone and exenatide in normal and diabetic rat islets exposed to lipotoxicity.
abstract: BACKGROUND
  Hyperlipidaemia has been suggested to contribute by pro-apoptotic actions to the loss of beta-cell mass, its secretory defects, and thereby impaired beta-cell function in type 2 diabetes. Treatment of genetically diabetic rats and also type 2 diabetic patients with pioglitazone, a PPAR-gamma agonist, lowers fasting levels of plasma glucose and triglycerides, and has been suggested to protect beta-cells against diabetic lipotoxicity in vitro and in vivo. Another recently launched anti-diabetic drug, exenatide, an incretin mimetic, has been shown to stimulate insulin secretion, growth, and proliferation of pancreatic beta-cells and to protect them against apoptosis. We aimed to investigate global alterations in beta-cell gene expression under lipotoxic conditions and the influence of in vitro treatment with pioglitazone and exenatide.
  
  
  METHODS
  Global gene expression profiling was thus performed to characterize genes differently regulated by palmitate, pioglitazone, and exenatide in isolated islets from non-diabetic Wistar rats and type 2 diabetic Goto-Kakizaki (GK) rats.
  
  
  RESULTS
  Gene expression profiling revealed significant changes in islet mRNAs involved in control of several aspects of beta-cell function, e.g. epigenetic regulation of gene expression, cell differentiation and morphogenesis, also metabolism, response to stimulus, transport, and signal transduction. Pioglitazone and exenatide appear to significantly impact epigenetic processes, e.g. stable alterations in gene expression potential, which arise during development and cell proliferation. Bcl2-like 1 (Bcl2l1), an anti-apoptotic protein, and Bcl2 modifying factor (Bmf), a pro-apoptotic protein, were both down-regulated by pioglitazone and exenatide in the presence of palmitate in diabetic GK islets. In contrast, Bmf was downregulated by pioglitazone in the presence of palmitate in non-diabetic Wistar islets. Exposure of non-diabetic Wistar islets to palmitate led to a reduction in the expression of PPAR beta/delta. This suggests that palmitate may increase the accumulation of triglycerides by reducing PPAR signalling. Moreover, treatment with either pioglitazone or exenatide restored and increased the expression of PPAR beta/delta in non-diabetic Wistar islets.
  
  
  CONCLUSIONS
  Taking into account that these drugs target different components of the epigenetic machinery, our findings suggest that they might participate in restoring normal gene activity in dysfunctional islets and that additive benefits may occur. Whether such events contribute to the beta-cell sparing, proliferative, and anti-apoptotic effects of these drugs in diabetes remains to be elucidated.
authors.affiliation: Karolinska Institutet, Department of Internal Medicine, Stockholm South Hospital, Stockholm, Sweden.
authors.forename: Hamedeh
authors.initials: H
authors.lastname: Ghanaat-Pour
authors.forename: Ake
authors.initials: A
authors.lastname: Sjöholm
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000473:pathology*; D000077270:Exenatide; D005786:Gene Expression Regulation / Q000187:drug effects*; D005941:Glucokinase / Q000235:genetics; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000473:pathology*; D008297:Male; D010455:Peptides / Q000494:pharmacology*; D000077205:Pioglitazone; D011506:Proteins / Q000235:genetics; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D051381:Rats; D017208:Rats, Wistar; D045162:Thiazolidinediones / Q000494:pharmacology*; D014688:Venoms / Q000494:pharmacology*
chemical_list: D007004:Hypoglycemic Agents; D010455:Peptides; D011506:Proteins; D045162:Thiazolidinediones; D014688:Venoms; D012313:RNA; D000077270:Exenatide; D005941:Glucokinase; D000077205:Pioglitazone