The insulin receptor (IR) mediates both metabolic and mitogenic effects especially when overexpressed or in clinical conditions with compensatory hyperinsulinemia, due to the metabolic pathway resistance, as obesity diabetes. In many cancers, IR is overexpressed preferentially as IR-A isoform, derived by alternative splicing of exon 11. The IR-A overexpression, and the increased IR-A:IR-B ratio, are mechanisms that promote the mitogenic response of cancer cells to insulin and IGF-2, which is produced locally by both epithelial and stromal cancer cells. In cancer IR-A, isoform predominance may occur for dysregulation at both mRNA transcription and post-transcription levels, including splicing factors, non-coding RNAs and protein degradation. The mechanisms that regulate IR isoform expression are complex and not fully understood. The IR isoform overexpression may play a role in cancer cell stemness, in tumor progression and in resistance to target therapies. From a clinical point of view, the IR-A overexpression in cancer may be a determinant factor for the resistance to IGF-1R target therapies for this issue. IR isoform expression in cancers may have the meaning of a predictive biomarker and co-targeting IGF-1R and IR-A may represent a new more efficacious treatment strategy.

Diabetic retinopathy (DR) is one of the main causes of vision loss in middle-aged economically active people. Modifiable (i.e., hyperglycaemia, hypertension, hyperlipidaemia, obesity, and cigarette smoke) and non-modifiable factors (i.e., duration of diabetes, puberty, pregnancy and genetic susceptibility) are involved in the development of DR. Epigenetic mechanisms, modulating the oxidative stress, inflammation, apoptosis, and aging, could influence the course of DR. Herein, we conducted a systematic review of observational studies investigating how epigenetics affects type 2 diabetes retinopathy (T2DR). A total of 23 epidemiological studies were included: 14 studies focused on miRNA, 4 studies on lnc-RNA, one study on both miRNA and lnc-RNA, and 4 studies on global or gene-specific DNA methylation. A direct relation between the dysregulation of miR-21, miR-93, and miR-221 and FPG, HbA1c, and HOMA-IR was identified. A panel of three miRNAs (hsa-let-7a-5p, hsa-miR-novel-chr5_15976, and hsa-miR-28-3p) demonstrated a good sensitivity and specificity for predicting T2DR. Little evidence is available regarding the possible role of the long non-coding MALAT1 dysregulation and MTHFR gene promoter hypermethylation. Despite these initial, encouraging findings potentially suggesting a role of epigenetics in T2DR, the use in clinical practice for the diagnosis and staging of this complication encounters several difficulties and further targeted investigations are still necessary.

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