Posttranscriptional regulation of the prostaglandin E receptor spliced-isoform EP3-γ and its implication in pancreatic ß-cell failure.

In Type 2 diabetes (T2D), elevated lipid levels have been suggested to contribute to insulin resistance and ß-cell dysfunction. We previously reported that the expression of the PGE2 receptor EP3 is elevated in islets of T2D individuals and is preferentially stimulated by palmitate, leading to ß-cell failure. The mouse EP3 receptor generates three isoforms by alternative splicing which differ in their C-terminal domain and are referred to as mEP3α, mEP3ß, and mEP3γ. We bring evidence that the expression of the mEP3γ isoform is elevated in islets of diabetic db/db mice and is selectively upregulated by palmitate. Specific knockdown of the mEP3γ isoform restores the expression of ß-cell-specific genes and rescues MIN6 cells from palmitate-induced dysfunction and apoptosis. This study indicates that palmitate stimulates the expression of the mEP3γ by a posttranscriptional mechanism, compared to the other spliced isoforms, and that the de novo synthesized ceramide plays an important role in FFA-induced mEP3γ expression in ß-cells. Moreover, induced levels of mEP3γ mRNA by palmitate or ceramide depend on p38 MAPK activation. Our findings suggest that mEP3γ gene expression is regulated at the posttranscriptional level and defines the EP3 signaling axis as an important pathway mediating ß-cell-impaired function and demise.

NF-κB activity during pancreas development regulates adult ß-cell mass by modulating neonatal ß-cell proliferation and apoptosis.

NF-κB is a well-characterized transcription factor, widely known for its roles in inflammation and immune responses, as well as in control of cell division and apoptosis. However, its function in ß-cells is still being debated, as it appears to depend on the timing and kinetics of its activation. To elucidate the temporal role of NF-κB in vivo, we have generated two transgenic mouse models, the ToIß and NOD/ToIß mice, in which NF-κB activation is specifically and conditionally inhibited in ß-cells. In this study, we present a novel function of the canonical NF-κB pathway during murine islet ß-cell development. Interestingly, inhibiting the NF-κB pathway in ß-cells during embryogenesis, but not after birth, in both ToIß and NOD/ToIß mice, increased ß-cell turnover, ultimately resulting in a reduced ß-cell mass. On the NOD background, this was associated with a marked increase in insulitis and diabetes incidence. While a robust nuclear immunoreactivity of the NF-κB p65-subunit was found in neonatal ß-cells, significant activation was not detected in ß-cells of either adult NOD/ToIß mice or in the pancreata of recently diagnosed adult T1D patients. Moreover, in NOD/ToIß mice, inhibiting NF-κB post-weaning had no effect on the development of diabetes or ß-cell dysfunction. In conclusion, our data point to NF-κB as an important component of the physiological regulatory circuit that controls the balance of ß-cell proliferation and apoptosis in the early developmental stages of insulin-producing cells, thus modulating ß-cell mass and the development of diabetes in the mouse model of T1D.

Predicting Weight Loss and Comorbidity Improvement 7 Years Following Laparoscopic Sleeve Gastrectomy: Does Early Weight Loss Matter?

BACKGROUND: Predicting the variables that affect the outcomes following laparoscopic sleeve gastrectomy (LSG) would allow focused resource allocation with a view to improving results. Whilst greater early post-operative weight loss following LSG is associated with greater short-term weight loss, the relationship between early results and long-term outcomes has not been described. METHODS: A retrospective cohort analysis was performed on patients who underwent LSG 7 years before a follow-up telephone interview was performed. Multivariate regression analysis was used to explore the relationship between early weight loss at 4 weeks following surgery and weight loss at 7 years. A non-inferiority analysis assessed whether early weight loss was associated with either improvement or resolution of hypertension or type 2 diabetes mellitus (T2DM) at 7 years after surgery. RESULTS: Of the 156 patients identified between April and October 2012, 130 (83.3%) met the inclusion criteria and were included in the analysis. The average preoperative BMI was 42.5 kg/m2 (standard deviation 5.2). The change in BMI was 4.6 kg/m2 (4.0) at 4 weeks and 12.2 kg/m2 (5.4) at 7 years. There was improvement or resolution in 19/31 (61.3%) patients with T2DM and 14/26 (53.8%) patients with hypertension. Whilst younger age was associated with greater weight loss at 7 years follow-up, no such relationship was identified with early post-operative weight loss. Early post-operative weight loss was also not associated with long-term improvement or resolution in hypertension or T2DM. CONCLUSIONS: Early weight loss does not appear to be associated with greater weight loss nor comorbidity improvement 7 years following LSG. TRIAL REGISTRATION: ClinicalTrials.gov (SZMC-95/19).