| Summary: | Insulin is amongst the human genome’s most well-studied genes/proteins due to its connection to metabolic health. Within this article, we review literature and data to build a knowledge base of Insulin (<i>INS</i>) genetics that influence transcription, transcript processing, translation, hormone maturation, secretion, receptor binding, and metabolism while highlighting the future needs of insulin research. The <i>INS</i> gene region has 2076 unique variants from population genetics. Several variants are found near the transcriptional start site, enhancers, and following the <i>INS</i> transcripts that might influence the readthrough fusion transcript <i>INS–IGF2</i>. This <i>INS–IGF2</i> transcript splice site was confirmed within hundreds of pancreatic RNAseq samples, lacks drift based on human genome sequencing, and has possible elevated expression due to viral regulation within the liver. Moreover, a rare, poorly characterized African population-enriched variant of INS–IGF2 results in a loss of the stop codon. <i>INS</i> transcript UTR variants rs689 and rs3842753, associated with type 1 diabetes, are found in many pancreatic RNAseq datasets with an elevation of the 3′UTR alternatively spliced <i>INS</i> transcript. Finally, by combining literature, evolutionary profiling, and structural biology, we map rare missense variants that influence preproinsulin translation, proinsulin processing, dimer/hexamer secretory storage, receptor activation, and C-peptide detection for quasi-insulin blood measurements.
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