Rabbit Anti-Human IR/IGF1R (phospho Tyr1162, Tyr1163) monoclonal antibody, clone 08I0M8

Aims/hypothesis Individuals who had a low birthweight (LBW) are at an increased risk of insulin resistance and type 2 diabetes when exposed to high-fat overfeeding (HFO). We studied genome-wide mRNA expression and DNA methylation in subcutaneous adipose tissue (SAT) after 5 days of HFO and after a control diet in 40 young men, of whom 16 had LBW. Methods mRNA expression was analysed using Affymetrix Human Gene 1.0 ST arrays and DNA methylation using Illumina 450K BeadChip arrays. Results We found differential DNA methylation at 53 sites in SAT from LBW vs normal birthweight (NBW) men (false discovery rate < 5%), including sites in the FADS2 and CPLX1 genes previously associated with type 2 diabetes. When we used reference-free cell mixture adjustments to potentially adjust for cell composition, 4,323 sites had differential methylation in LBW vs NBW men. However, no differences in SAT gene expression levels were identified between LBW and NBW men. In the combined group of all 40 participants, 3,276 genes (16.5%) were differentially expressed in SAT after HFO (false discovery rate < 5%) and there was no difference between LBW men and controls. The most strongly upregulated genes were ELOVL6, FADS2 and NNAT; in contrast, INSR, IRS2 and the SLC27A2 fatty acid transporter showed decreased expression after HFO. Interestingly, SLC27A2 expression correlated negatively with diabetes- and obesity-related traits in a replication cohort of 142 individuals. DNA methylation at 652 CpG sites (including in CDK5, IGFBP5 and SLC2A4) was altered in SAT after overfeeding in this and in another cohort. Conclusions/interpretation Young men who had a LBW exhibit epigenetic alterations in their adipose tissue that potentially influence insulin resistance and risk of type 2 diabetes. Short-term overfeeding influences gene transcription and, to some extent, DNA methylation in adipose tissue; there was no major difference in this response between LBW and control participants.

Disruption of brain insulin signaling may explain the higher Alzheimer's disease (AD) risk among type 2 diabetic (T2D) patients. There is evidence from in vitro and human postmortem studies that combination of insulin with hypoglycemic medications is neuroprotective and associated with less amyloid aggregation. We examined the effect of 8-month intranasal administration of insulin, exenatide (a GLP-1 agonist), combination therapy (insulin + exenatide) or saline, in wild-type (WT) and an AD-like mouse model (Tg2576). Mice were assessed for learning, gene expression of key mediators and effectors of the insulin receptor signaling pathway (IRSP-IRS1, AKT1, CTNNB1, INSR, IRS2, GSK3B, IGF1R, AKT3), and brain Amyloid Beta (A) levels. In Tg2576 mice, combination therapy reduced expression of IRSP genes which was accompanied by better learning. Cortical A levels were decreased by 15-30% in all groups compared to saline but this difference did not reach statistical significance. WT mice groups, with or without treatment, did not differ in any comparison. Disentangling the mechanisms underlying the potential beneficial effects of combination therapy on the IR pathway and AD-like behavior is warranted.