Research Helps Improve Treatment of Diabetes Mellitus

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UKZN and University of Pretoria scientists have discovered how inherited mutations in the insulin gene lead to defective binding to the insulin receptor thereby resulting in diabetes mellitus.

The study, a world first, paves the way for a better understanding and treatment of this lifestyle disease, otherwise known as a “silent killer”. The paper was recently published in the Journal of Biomolecular Structure and Dynamics.

Insulin plays a central role in the regulation of human metabolism. There are three inherited mutations in the insulin gene referred to as insulins Wakayama, Los Angeles and Chicago after the cities in which they were discovered. These inherited mutations in the insulin gene lead to defective binding to the insulin receptor thereby resulting in diabetes mellitus.

The study aimed to indicate, at the molecular level, how the mutations affect the contact points in the receptor much like the way a defective key can fail to open a lock.

Through a pharmacoinformatics analysis, the study found that due to the small size and less surface area of the replaced amino acids, the binding interactions were reduced and this altered the binding affinity towards the insulin receptor. In order to confirm the possible reason for this, a molecular dynamics (MD) study was also performed.

The MD study observed that the insulin part of native insulin, Chicago and Los Angeles, still maintain the stable interaction with the insulin receptor (IR) but a complete dissociation of the insulin from IR was observed for insulin Wakayama during the MD simulation.

The PC analysis also showed that the highest contribution of the insulin residues to the two distinct conformational variances observed along both PC1 and PC2 was found in the complex of insulin Wakayama and the next significant contribution was observed in the complex with native insulin.

Therefore the trajectories of the MD successfully explained that possible reasons may be the smaller size and variation of the size chains of the amino acids which affects the binding interactions as well as the stability of the complex.

The results of the study are exciting as it indicates how these defective molecules bind to the insulin receptor paving the way to a better understanding and the development of new analogues that can be used to activate the insulin receptor and treat diabetes mellitus.

Head of the Department of Chemical Pathology at the University of Pretoria, Professor Tahir S Pillay, commented on the findings: ‘The study arose out of my longstanding research interest in the insulin receptor signalling pathway.  The insulin receptor is the gateway to the control of glucose metabolism.  We were able to exploit the published crystal structures of normal insulin bound to the insulin receptor to perform the modelling studies. Understanding how these mutant insulins make contact and which parts of the receptor are required for activation by insulin when compared  to normal insulin, will provide a greater understanding how insulin-like analogues could be engineered or small molecule agonists synthesised to mimic the actions of normal insulin for the treatment of diabetes mellitus.’

Principal Investigator of the study from UKZN, Professor Mahmoud Soliman, said, ‘In this collaborative work with scientists from the University of Pretoria, cutting-edge bioinformatics and molecular modelling tools, which is the main focus of my research at UKZN, are being applied in order to understand the molecular mechanism by which the inherited mutations in the insulin gene can lead to defective binding to the insulin receptor thereby resulting in diabetes mellitus, a phenomena that has been vague in literature for quite a long time. The outcome of the study will definitely help scientists from various research domains understand the mechanism of binding, hence, develop more potent insulin analogues that can treat diabetes mellitus.’

MaryAnn Francis