Hyperproinsulinemia in a three-generation Caucasian family due to mutant proinsulin (Arg{sup 65}{yields}His) not associated with impaired glucose tolerance: The contribution of mutant proinsulin to insulin bioactivity

Journal Article · Mon Apr 01 04:00:00 EST 1996 · Journal of Clinical Endocrinology and Metabolism

DOI:https://doi.org/10.1210/jc.81.4.1634· OSTI ID:530767

Roder, M E; Vissing, H ^[1]; Nauck, M A ^[2]

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1. Health Care Discovery, Bagsvaerd (Denmark)
2. Ruhr-Univ. Bochum (Germany)

Familial hyperproinsulinemia is a genetic abnormality characterized by an increased proportion of proinsulin immunoreactivity in the circulation due to mutations affecting the posttranslational processing of proinsulin. In affected Japanese families, this has been associated with noninsulin-dependent diabetes mellitus or impaired glucose tolerance. A three-generation Caucasian family with hyperproinsulinemia was identified through unexplained hyperinsulinemia in a normal volunteer participating in a metabolic study. High pressure liquid chromatography analysis of fasting plasma revealed a major peak eluting close to the position of proinsulin. Direct sequencing of the proinsulin gene exon 3 showed a heterozygous point mutation (CGT{yields}CAT) resulting in the substitution of Arg{yields}His in position 65 (corresponding to the AC cleavage site) in the index case, his mother, and his maternal grandmother. All affected subjects had normal oral glucose tolerance. In the basal state and after oral glucose administration, their proinsulin responses were slightly reduced. However, when calculating insulin bioactivity by assuming 9% activity for mutant Arg{sup 65}{yields}His proinsulin, responses in affected subjects were comparable to those in normal subjects. In conclusion, our data demonstrate hyperproinsulinemia in a three-generation Caucasian family due to heterozygous mutant Arg{sup 65}{yields}His proinsulin. This was not associated with impaired glucose tolerance. These results suggest that this mutation in the heterozygous state per se does not affect glucose tolerance and that the biological activity of mutant proinsulin contributes to glucose homeostasis in this family. The association of the same mutation with impaired glucose tolerance or diabetes in previous studies may be the result of selection bias or associated conditions (e.g. the genetic background of the kindreds examined). 29 refs., 5 figs., 3 tabs.

• OSTI ID: 530767
• Journal Information: Journal of Clinical Endocrinology and Metabolism, Journal Name: Journal of Clinical Endocrinology and Metabolism Journal Issue: 4 Vol. 81; ISSN JCEMAZ; ISSN 0021-972X
• Country of Publication: United States
• Language: English

Related Subjects

55 BIOLOGY AND MEDICINE
BASIC STUDIES
AMINO ACIDS
DIABETES MELLITUS
DNA SEQUENCING
GENE MUTATIONS
GENES
GENETICS
GLUCOSE
HEREDITARY DISEASES
HOMEOSTASIS
IMMUNOASSAY
INSULIN
METABOLIC DISEASES
METABOLISM
NUCLEOTIDES
PATIENTS
STATISTICS