Insulin Wakayama: Mutant insulin syndrome in Japan

Nanjo, K; Kondo, Minoru; Sanke, Tokio; Nishimura, Susumu; Miyano, M; Okai, Kazuhiko; Sowa, R; Nishi, Masami; Miyamura, Kei; Inouye, Karen

doi:10.1016/0168-8227(87)90062-3

Cited by 13 publications

(22 citation statements)

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“…Both A3Val and B12Val are involved in insulinreceptor interaction (2)(3)(4)(5). Insulin Wakayama, in which A3Val was replaced by Leu, is a natural mutant with very low biological activity (6). However, A3Val can be replaced by the hydrophilic Thr residue with almost complete retention of biological activity, perhaps due to the similar shape and bulk of Val and Thr (7 ).…”

Section: Introductionmentioning

confidence: 99%

Mutational Analysis of the Three Conserved Valine Residues of Insulin and a Proposal of “Isosteric Residue”

Guo¹,

Tang²,

Zhang³

et al. 2001

IUBMB Life

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Section: Introductionmentioning

confidence: 99%

Mutational Analysis of the Three Conserved Valine Residues of Insulin and a Proposal of “Isosteric Residue”

Guo¹,

Tang²,

Zhang³

et al. 2001

IUBMB Life

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“…Elevation of circulating proinsulin and the processing intermediates is observed in a number of pathophysiological situations including the prodrome of type 1 diabetes (Heaton et al 1988), mild type 2 diabetes (Clark et al 1992), glucose-intolerant states (Davies et al 1993), pancreatic duct obstruction, thyroid disease (Beer et al 1989) and insulin resistance induced by corticosteroids (Ward et al 1987). More pronounced proinsulinemia is associated with genetic mutations in the proinsulin molecule (Nanjo et al 1987, Roder et al 1996, proinsulin-processing enzyme defects (Naggert et al 1995, Jackson et al 1997, Furuta et al 1998) and pancreatic adenomas (Cohen et al 1986). (Proinsulinemia is defined here as conditions where either the proinsulin molecule or any of the common processing intermediates (split 32,33 proinsulin, des 31,32 proinsulin, split 65,66 proinsulin, des 64,65 proinsulin) are elevated more than 2-fold.)…”

Section: Introductionmentioning

confidence: 99%

Proinsulin processing in the diabetic Goto-Kakizaki rat

Guest¹,

Abdel‐Halim²,

Gross³

et al. 2002

Journal of Endocrinology

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The biosynthesis and processing of proinsulin was investigated in the diabetic Goto-Kakizaki (GK) rat. Immunofluorescence microscopy comparing GK and Wistar control rat pancreata revealed marked changes in the distribution of -cells and pronounced -cell heterogeneity in the expression patterns of insulin, prohormone convertases PC1, PC2, carboxypeptidase E (CPE) and the PC-binding proteins 7B2 and ProSAAS. Western blot analyses of isolated islets revealed little difference in PC1 and CPE expression but PC2 immunoreactivity was markedly lower in the GK islets. The processing of the PC2-dependent substrate chromogranin A was reduced as evidenced by the appearance of intermediates. No differences were seen in the biosynthesis and post-translational modification of PC1, PC2 or CPE following incubation of islets in 16·7 mM glucose, but incubation in 3·3 mM glucose resulted in decreased PC2 biosynthesis in the GK islets. The rates of biosynthesis, processing and secretion of newly synthesized (pro)insulin were comparable. Circulating insulin immunoreactivity in both Wistar and GK rats was predominantly insulin 1 and 2 in the expected ratios with no (pro)insulin evident. Thus, the marked changes in islet morphology and PC2 expression did not impact the rate or extent of proinsulin processing either in vitro or in vivo in this experimental model.

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“…10 families have been reported in which some members have single point mutations in the insulin gene that result in amino acid substitutions within the proinsulin molecule. Among them, six families have mutations in which the abnormal insulin has essentially normal immunoreactivity but is biologically defective; in three Japanese families A3-Val was replaced with Leu (insulin Wakayama [6][7][8]); in two independent families in the United States and Canada B24-Phe was replaced with Ser (insulin Los Angeles [9][10][11]); and in a single family in the United States B25-Phe was replaced with Leu (insulin Chicago [12,13]). Few additional families have been identified in which the mutations are associated with hyperproinsulinemia.…”

Section: Introductionmentioning

confidence: 99%

A novel point mutation in the human insulin gene giving rise to hyperproinsulinemia (proinsulin Kyoto).

Yano¹,

Kitano²,

Morimoto³

et al. 1992

J. Clin. Invest.

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We have identified a 65-yr-old nonobese Japanese man with diabetes mellitus, fasting hyperinsulinemia (150-300 pM), and a reduced fasting C-peptide/insulin molar ratio of 2.5-3.0. Fasting hyperinsulinemia was also found in his son and daughter. Analysis of insulin isolated from the serum of the proband and his son by reverse-phase high performance liquid chromatography revealed a minor peak coeluting with human insulin and a major peak of proinsulin-like materials. The insulin gene of the patient was amplified by the polymerase chain reaction and the products were sequenced. A novel point mutation was identified in which guanine was replaced by thymine. The substitution gives rise to a new HindI1 recognition site and results in the amino acid replacement of leucine for arginine at position 65. These results indicate that the amino-acid replacement prevents recognition of the C-peptide-A chain dibasic protease and results in an elevation of proinsulin-like materials in the circulation. Furthermore, in this family the proinsulin-like materials is due to a biosynthetic defect, inherited as an autosomal dominant trait. Rapid detection of this mutation can be accomplished by HindIII restriction enzyme mapping of polymerase chain reaction-generated DNA, which enables us to facilitate the diagnosis and screening. (J. Clin. Invest. 1992. 89:1902-1907

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Insulin Wakayama: Mutant insulin syndrome in Japan

Cited by 13 publications

References 0 publications

Mutational Analysis of the Three Conserved Valine Residues of Insulin and a Proposal of “Isosteric Residue”

Mutational Analysis of the Three Conserved Valine Residues of Insulin and a Proposal of “Isosteric Residue”

Proinsulin processing in the diabetic Goto-Kakizaki rat

A novel point mutation in the human insulin gene giving rise to hyperproinsulinemia (proinsulin Kyoto).

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