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      Conformational Dynamics of Insulin

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          Abstract

          We have exploited a prandial insulin analog to elucidate the underlying structure and dynamics of insulin as a monomer in solution. A model was provided by insulin lispro (the active component of Humalog ®; Eli Lilly and Co.). Whereas NMR-based modeling recapitulated structural relationships of insulin crystals (T-state protomers), dynamic anomalies were revealed by amide-proton exchange kinetics in D 2O. Surprisingly, the majority of hydrogen bonds observed in crystal structures are only transiently maintained in solution, including key T-state-specific inter-chain contacts. Long-lived hydrogen bonds (as defined by global exchange kinetics) exist only at a subset of four α-helical sites (two per chain) flanking an internal disulfide bridge (cystine A20–B19); these sites map within the proposed folding nucleus of proinsulin. The anomalous flexibility of insulin otherwise spans its active surface and may facilitate receptor binding. Because conformational fluctuations promote the degradation of pharmaceutical formulations, we envisage that “dynamic re-engineering” of insulin may enable design of ultra-stable formulations for humanitarian use in the developing world.

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          Insulin gene mutations as a cause of permanent neonatal diabetes.

          We report 10 heterozygous mutations in the human insulin gene in 16 probands with neonatal diabetes. A combination of linkage and a candidate gene approach in a family with four diabetic members led to the identification of the initial INS gene mutation. The mutations are inherited in an autosomal dominant manner in this and two other small families whereas the mutations in the other 13 patients are de novo. Diabetes presented in probands at a median age of 9 weeks, usually with diabetic ketoacidosis or marked hyperglycemia, was not associated with beta cell autoantibodies, and was treated from diagnosis with insulin. The mutations are in critical regions of the preproinsulin molecule, and we predict that they prevent normal folding and progression of proinsulin in the insulin secretory pathway. The abnormally folded proinsulin molecule may induce the unfolded protein response and undergo degradation in the endoplasmic reticulum, leading to severe endoplasmic reticulum stress and potentially beta cell death by apoptosis. This process has been described in both the Akita and Munich mouse models that have dominant-acting missense mutations in the Ins2 gene, leading to loss of beta cell function and mass. One of the human mutations we report here is identical to that in the Akita mouse. The identification of insulin mutations as a cause of neonatal diabetes will facilitate the diagnosis and possibly, in time, treatment of this disorder.
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            Structural biology of insulin and IGF1 receptors: implications for drug design.

            Type 2 diabetes mellitus -- in which the body produces insufficient amounts of insulin or the insulin that is produced does not function properly to control blood glucose -- is an increasingly common disorder. Prospective clinical studies have proven the benefits of tighter glucose control in reducing the frequency and severity of complications of the disease, leading to the advocation of earlier and more aggressive use of insulin therapy. Given the reluctance of patients with type 2 diabetes to inject themselves with insulin, orally active insulin mimetics would be a major therapeutic advance. Here, we discuss recent progress in understanding the structure-function relationships of the insulin and insulin-like growth factor 1 (IGF1) receptors, their mechanism of activation and their implications for the design of insulin-receptor agonists for diabetes therapy and IGF1-receptor antagonists for cancer therapy.
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              New perspectives into the molecular pathogenesis and treatment of type 2 diabetes.

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                Author and article information

                Journal
                Front Endocrinol (Lausanne)
                Front Endocrinol (Lausanne)
                Front. Endocrin.
                Frontiers in Endocrinology
                Frontiers Research Foundation
                1664-2392
                04 September 2011
                18 October 2011
                2011
                : 2
                : 48
                Affiliations
                [1] 1simpleDepartment of Biochemistry, School of Medicine, Case Western Reserve University Cleveland, OH, USA
                Author notes

                Edited by: Kenneth Siddle, University of Cambridge, UK

                Reviewed by: Andrzej Marek Brzozowski, University of York, UK; Ramasamy Paulmurugan, Stanford University, USA

                *Correspondence: Michael A. Weiss, Department of Biochemistry, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue – Wood W436, Cleveland, OH 44106-4935, USA. e-mail: michael.weiss@ 123456case.edu

                This article was submitted to Frontiers in Molecular and Structural Endocrinology, a specialty of Frontiers in Endocrinology.

                Article
                10.3389/fendo.2011.00048
                3355934
                22649374
                3c53a3d3-4df7-4f87-9880-c2c3f9cc3efa
                Copyright © 2011 Hua, Jia and Weiss.

                This is an open-access article subject to a non-exclusive license between the authors and Frontiers Media SA, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and other Frontiers conditions are complied with.

                History
                : 17 August 2011
                : 18 September 2011
                Page count
                Figures: 8, Tables: 1, Equations: 1, References: 92, Pages: 11, Words: 9765
                Categories
                Endocrinology
                Original Research

                Endocrinology & Diabetes
                protein dynamics,hydrogen bond,diabetes mellitus,amide-proton exchange,protein engineering,nmr spectroscopy,protein therapeutics,protein structure

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