Receptor-isoform-selective insulin analogues give tissue-preferential effects

Abstract

The relative expression patterns of the two IR (insulin receptor) isoforms, +/- exon 11 (IR-B/IR-A respectively), are tissue-dependent. Therefore we have developed insulin analogues with different binding affinities for the two isoforms to test whether tissue-preferential biological effects can be attained. In rats and mice, IR-B is the most prominent isoform in the liver (> 95%) and fat (> 90%), whereas in muscles IR-A is the dominant isoform (> 95%). As a consequence, the insulin analogue INS-A, which has a higher relative affinity for human IR-A, had a higher relative potency [compared with HI (human insulin)] for glycogen synthesis in rat muscle strips (26%) than for glycogen accumulation in rat hepatocytes (5%) and for lipogenesis in rat adipocytes (4%). In contrast, the INS-B analogue, which has an increased affinity for human IR-B, had higher relative potencies (compared with HI) for inducing glycogen accumulation (75%) and lipogenesis (130%) than for affecting muscle (45%). For the same blood-glucose-lowering effect upon acute intravenous dosing of mice, INS-B gave a significantly higher degree of IR phosphorylation in liver than HI. These in vitro and in vivo results indicate that insulin analogues with IR-isoform-preferential binding affinity are able to elicit tissue-selective biological responses, depending on IR-A/IR-B expression.

IGF1 and IGF2 specificities to the two insulin receptor isoforms are determined by insulin receptor amino acid 718

“…The two IR isoforms differ by the absence (IR-A) or the presence (IR-B) of the exon 11 encoded 12 amino acids at the C-terminal part of the α subunit and the relative isoform abundance is regulated at the pre-mRNA level by alternative splicing of exon 11 [4]. The ratio between the two isoforms of IR varies between different tissues [5] [6], where IR-A is highly expressed in human kidney and brain, while IR-B is the predominant isoform in human liver [7]. Alternative splicing is hormonally regulated and is altered during development and under a number of pathological conditions such as type 2 diabetes and cancer [8].…”

Structural Perspectives of Insulin Receptor Isoform-Selective Insulin Analogs

“…They prepared a series of analogs modified at positions A8, B25, and B27. The (HisA8, AsnB25, GluB27-desThrB30)-insulin displayed about 26–30% of binding affinity for IR-B and 8–10% for IR-A (10, 46), which resulted in approximately fourfold enhanced IR-B/IR-A binding selectivity, in comparison with human insulin. Interestingly, it seems that the binding preference of this analog for IR-B was achieved rather by diminishing its binding affinity for IR-A than by enhancing it for IR-B.…”

“…This differential sequence, which represents only a small fragment of IR (1,380 amino acids in total), has a relatively subtle impact on ligand binding and intracellular signaling, but which may nevertheless have important physiological consequences. Both isoforms have different tissue distribution with the longer IR-B being the largely predominant form in adult humans in hepatocytes (more than 90%), skeletal muscle and subcutaneous fat (both about 70% IR-B) (10), while the shorter IR-A is almost exclusively expressed in other tissues (e.g., brain, lymphatic tissues, or embryo) [Ref. (11) and the references herein].…”

“…Nevertheless, the biological data obtained with insulin and IGF analogs could be useful in the prediction or design of specific interactions of the αCT-B segment. The Novo Nordisk A/S research group presented the first attempts at designing IR-B selective insulin analogs in 2011 (10, 46). They prepared a series of analogs modified at positions A8, B25, and B27.…”

Insulin signalling to the kidney in health and disease

“…Recently, it has also been shown that kidney, as a whole, abundantly expresses IR isoform B [60], which is the isoform found in the classically insulin-responsive, glucose-regulating, tissues of fat, skeletal muscle and liver. It is now also clear that insulin is involved in a number of homoeostatic physiological responses throughout the kidney and are described below.…”