Gene expression regulated by pioglitazone and exenatide in normal and diabetic rat islets exposed to lipotoxicity.

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.

Lack of correlation between the reduction of serum immunoglobulin concentration and the CTG repeat expansion in patients with type 1 dystrophia [correction of Dystrofia] myotonica.

The length of the CTG repeat in the 3' untranslated region of the DMPK gene is considered to be associated with clinical severity in type 1 Dystrofia Myotonica (DM1) and has also been suggested to correlate with the degree of deficiency of IgG noted in these patients. Total serum level of IgG and IgG subclasses was therefore measured in 61 Swedish patients with DM1, the largest number of patients investigated to date in this respect. Almost half (44%) of the DM1 patients showed a serum concentration of IgG below the normal range. Deficiency of IgG1, IgG2 or IgG3 was noted in 26%, 7% and 20% of the patients, respectively. As transcription of genes 3' of the DMPK gene on chromosome 19 is reduced in DM1 patients, a decreased expression of the alpha chain of the receptor involved in IgG catabolism, FcRn, may theoretically be responsible for the low serum IgG in DM1 patients. No correlation was however found between the number of CTG repeats, levels of FcRn transcripts in either muscle tissue or lymphocytes and serum IgG levels.

Global expression profiling of glucose-regulated genes in pancreatic islets of spontaneously diabetic Goto-Kakizaki rats.

The spontaneously diabetic Goto-Kakizaki (GK) rat is frequently used as a model for human type 2 diabetes. Selective loss of glucose-sensitive insulin secretion is an early pathogenetic event in human type 2 diabetes, and such a defect also typifies islets from the GK rat. We investigated whether expression of specific glucose-regulated genes is disturbed in islets from GK rats when compared with Wistar rats. Large-scale gene expression analysis using Affymetrix microarrays and qRT-PCR measurements of mRNA species from normal and diabetic islets were performed after 48 h of culture at 3 or 20 mM glucose. Of the 2020 transcripts differentially regulated in diabetic GK islets when compared with controls, 1033 were up-regulated and 987 were down-regulated. We identified significant changes in islet mRNAs involved in glucose sensing, phosphorylation, incretin action, glucocorticoid handling, ion transport, mitogenesis, and apoptosis that clearly distinguish diabetic animals from controls. Such markers may provide clues to the pathogenesis of human type 2 diabetes and may be of predictive and therapeutical value in clinical settings in efforts aiming at conferring beta-cell protection against apoptosis, impaired regenerative capacity and functional suppression occurring in diabetes.