Insulin Wakayama: familial mutant insulin syndrome in Japan

Nanjo, Kishio; Miyano, Motoshige; Kondo, Mizuho; Sanke, Tokio; Nishimura, Susumu; Miyamura, Kei; Inouye, Ken; Given, B. D.; Chan, Shu Jin; Polonsky, Kenneth S.; Tager, Howard S.; Steiner, Donald F.; Rubenstein, Arthur H.

doi:10.1007/bf00274577

Cited by 27 publications

(3 citation statements)

References 25 publications

(36 reference statements)

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“…Some mutations that show glucose intolerance or syndrome of mild diabetes are as a result of the substitution of B25-Phe with Leu (Chicago), A3-Val with Leu (Los Angeles) or B24-Phe with Ser (Wakayama). The four proinsulin mutations which are proinsulin Providence (H34D), proinsulin Tokyo (R89H), proinsulin Kyoto (R89L), and proinsulin Oxford (R89P) also show mild symptoms [100,101]. Such individuals with those mutations are diagnosed with the synthesis of biologically impaired insulin in their receptor binding potency due to changes of A or B chains.…”

Section: The Severity Of the Diseasementioning

confidence: 99%

The heterogeneity of diabetes, a silent pandemic: the essence of one health approach and precision medicine in the fight against diabetes

Marshall¹,

Bu²

2023

Preprint

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Life is supported by metabolism, a vital physiological activity. It guarantees enough energy available to power every cellular activity. The primary cellular substrate, glucose, is where the majority of the energy needed by the cell to support all other life activities and the growth of living creatures is derived. The quality of life is greatly impacted by any disease or flaw that alters the metabolism of glucose. There is no known cure for the metabolic illness known as diabetes. As diabetes is so varied, the only effective treatments would be based on precision medicine and a molecular strategy. This review covers a wide range of topics, including the ability to recognize the various forms of diabetes, the anthropogenic and genetic influence of the cause of diabetes, the severity of the various forms of diabetes, its potential existential risk, the disease burden, and clinical methods for diagnosing them. The most recent research goes on to recommend ways to ameliorate the disease, including diet-based management, biotherapies, and other individual lifestyle choices. Futuristic therapy using molecular biology approach was suggested. Recent research found a direct correlation between an individual's lifestyle and the rate of gene mutation in diabetes. There is an existential risk associated with the sickness as the rate of the spread of the disease among population globally is faster than the world's population growth rate. It is possible to think of diabetes as a silent pandemic.

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Section: The Severity Of the Diseasementioning

confidence: 99%

The heterogeneity of diabetes, a silent pandemic: the essence of one health approach and precision medicine in the fight against diabetes

Marshall¹,

Bu²

2023

Preprint

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“…Mutation of a conserved IR-interacting insulin residue would therefore be expected to negatively impact insulin's binding interactions with the IR. For example, the first three insulin variants clinically identified in patients, named Chicago (Phe B25 Leu) (40,41), Los Angeles (Phe B24 Ser) (42)(43)(44), and Wakayama (Val A3 Leu) (45)(46)(47)(48)(49) were found to alter insulin's binding affinity for the insulin receptor without significantly altering insulin's independent folding or processing (40,44,45,50,51). Notably, these three residues are highly conserved across all species (Fig.…”

Section: Introductionmentioning

confidence: 99%

A λ-dynamics investigation of insulinWakayamaand other A3 variant binding affinities to the insulin receptor

Barron,

Vilseck

2024

Preprint

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Insulin Wakayama is a clinical insulin variant where a conserved valine at the third residue on insulin's A chain (ValA3) is replaced with a leucine (LeuA3), impairing insulin receptor (IR) binding by 140-500 fold. This severe impact on binding from such a subtle modification has posed an intriguing problem for decades. Although experimental investigations of natural and unnatural A3 mutations have highlighted the sensitivity of insulin-IR binding to minor changes at this site, an atomistic explanation of these binding trends has remained elusive. We investigate this problem computationally using λ-dynamics free energy calculations to model structural changes in response to perturbations of the ValA3 side chain and to calculate associated relative changes in binding free energy (ΔΔGbind). The Wakayama LeuA3 mutation and seven other A3 substitutions were studied in this work. The calculated ΔΔGbind results showed high agreement compared to experimental binding potencies with a Pearson correlation of 0.88 and a mean unsigned error of 0.68 kcal/mol. Extensive structural analyses of λ-dynamics trajectories revealed that critical interactions were disrupted between insulin and the insulin receptor as a result of the A3 mutations. This investigation also quantifies the effect that adding an A3 Cδ atom or losing an A3 Cγ atom has on insulin's binding affinity to the IR. Thus, λ-dynamics was able to successfully model the effects of subtle modifications to insulin's A3 side chain on its protein-protein interactions with the IR and shed new light on a decades-old mystery: the exquisite sensitivity of hormone-receptor binding to a subtle modification of an invariant insulin residue.

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“… Mutation of a conserved IR-interacting insulin residue would therefore be expected to negatively impact insulin’s binding interactions with the IR. For example, the first three insulin variants clinically identified in patients, named Chicago (Phe B25 Leu), , Los Angeles (Phe B24 Ser), − and Wakayama (Val A3 Leu), − were found to alter insulin’s binding affinity for the insulin receptor without significantly altering insulin’s independent folding or processing. ,,,, Notably, these three residues are highly conserved across all species (Figure S1) and were later shown to directly contact the receptor. , Collectively, insulin Wakayama ’s Leu A3 mutation displayed the lowest binding affinity for the insulin receptor, with 140- to 500-fold worse binding affinity relative to native Val A3 insulin. ,, …”

Section: Introductionmentioning

confidence: 99%

A λ-Dynamics Investigation of Insulin Wakayama and Other A3 Variant Binding Affinities to the Insulin Receptor

Barron,

Vilseck

2024

J. Chem. Inf. Model.

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Insulin Wakayama is a clinical insulin variant where a conserved valine at the third residue on insulin's A chain (Val A3 ) is replaced with a leucine (Leu A3 ), weakening insulin receptor (IR) binding by 140−500-fold. This severe impact on binding from a subtle modification has posed an intriguing problem for decades. Although experimental investigations of natural and unnatural A3 mutations have highlighted the sensitivity of insulin−IR binding at this site, atomistic explanations of these binding trends have remained elusive. We investigate this problem computationally using λ-dynamics free energy calculations to model structural changes in response to perturbations of the Val A3 side chain and to calculate associated relative changes in binding free energy (ΔΔG bind ). The Wakayama Leu A3 mutation and seven other A3 substitutions were studied in this work. The calculated ΔΔG bind results showed high agreement compared to experimental binding potencies with a Pearson correlation of 0.88 and a mean unsigned error of 0.68 kcal/mol. Extensive structural analyses of λ-dynamics trajectories revealed that critical interactions were disrupted between insulin and the insulin receptor as a result of the A3 mutations. This investigation also quantifies the effect that adding an A3 C δ atom or losing an A3 C γ atom has on insulin's binding affinity to the IR. Thus, λ-dynamics was able to successfully model the effects of mutations to insulin's A3 side chain on its protein−protein interactions with the IR and shed new light on a decades-old mystery: the exquisite sensitivity of hormone−receptor binding to a subtle modification of an invariant insulin residue.

show abstract

Insulin Wakayama: familial mutant insulin syndrome in Japan

Cited by 27 publications

References 25 publications

The heterogeneity of diabetes, a silent pandemic: the essence of one health approach and precision medicine in the fight against diabetes

The heterogeneity of diabetes, a silent pandemic: the essence of one health approach and precision medicine in the fight against diabetes

A λ-dynamics investigation of insulinWakayamaand other A3 variant binding affinities to the insulin receptor

A λ-Dynamics Investigation of Insulin Wakayama and Other A3 Variant Binding Affinities to the Insulin Receptor

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