Sulfation pathways in the maintenance of functional beta-cell mass and implications for diabetes

Abstract

Diabetes Type 1 and Type 2 are widely occurring diseases. In spite of a vast amount of biomedical literature about diabetic processes in general, links to certain biological processes are only becoming evident these days. One such area of biology is the sulfation of small molecules, such as steroid hormones or metabolites from the gastrointestinal tract, as well as larger biomolecules, such as proteins and proteoglycans. Thus, modulating the physicochemical propensities of the different sulfate acceptors, resulting in enhanced solubility, expedited circulatory transit, or enhanced macromolecular interaction. This review lists evidence for the involvement of sulfation pathways in the maintenance of functional pancreatic beta-cell mass and the implications for diabetes, grouped into various classes of sulfated biomolecule. Complex heparan sulfates might play a role in the development and maintenance of beta-cells. The sulfolipids sulfatide and sulfo-cholesterol might contribute to beta-cell health. In beta-cells, there are only very few proteins with confirmed sulfation on some tyrosine residues, with the IRS4 molecule being one of them. Sulfated steroid hormones, such as estradiol-sulfate and vitamin-D-sulfate, may facilitate downstream steroid signaling in beta-cells, following de-sulfation. Indoxyl sulfate is a metabolite from the intestine, that causes kidney damage, contributing to diabetic kidney disease. Finally, from a technological perspective, there is heparan sulfate, heparin, and chondroitin sulfate, that all might be involved in next-generation beta-cell transplantation. Sulfation pathways may play a role in pancreatic beta-cells through multiple mechanisms. A more coherent understanding of sulfation pathways in diabetes will facilitate discussion and guide future research.

Keywords: beta-cells; diabetes; insulin; sulfate activation; sulfation pathways.

Figure 1. Short and long lasting insulin variants.

With regard to their molecular composition, established rapid-acting and long-acting insulins are compared with the newly introduced once-weekly insulin icodec. TyrA14Glu, TyrB16His, and PheB25His are mutations not contained in any of the commonly used insulins so far. The C14 acylation of detemir is myristic acid; the C16 acylation in degludec is hexadecanedioic acid; only the C20 acylation in icodec is more complex, two oligoethylene glycol units connect LysB29 to an oligoethylene icosanedioic diacid, via a gamma-glutamate moiety. Please note that detemir, degludec, and icodec all are ΔThrB30 insulins. Rapid and long insulins are presented according to [145], the insulin icodec molecule is described in [64].

Figure 2. Alignment of different insulin receptor substrates.

Protein sequences NP_005535 for IRS1, NP_003740 for IRS2, and NP_003595 for IRS4 were aligned using the multiple sequence alignment tool Muscle [146]. Sulfated IRS4 tyrosine Y921 corresponds to Y896 in IRS1 and Y919 in IRS2. Negatively charged amino acids depicted in red, positively charged ones, in blue.

Figure 3. Indoxyl-sulfate and related metabolites.

Molecular structures of tryptophan (showing the indole side chain only), of indoxyl-sulfate, and of para-cresyl-sulfate. Although indoxyl-sulfate and para-cresyl-sulfate are both produced in the intestine, they have different downstream effects.