Individuals with only one allele for a functional insulin receptor have a tendency to hyperinsulinaemia but not to hyperglycaemia

Abstract

Summary. Recently, we described a leprechaun patient with a genetically transmitted severe insulin resistance due to the absence of functional insulin receptors as inferred from the loss of insulin binding to the patients' fibroblasts and the impaired autophosphorylation of the [~-chain of the receptor. This patient was homozygous for the genetic defect which was recently found to be a leucine to proline mutation at position 233 in the a-chain of the insulin receptor. In the present study we have examined insulin receptor functions in relatives of this patient. Some of these individuals are heterozygous for the genetic defect and have only one allele coding for a functional insulin receptor. Insulin binding to cultured fibroblasts from the heterozygous individuals is only 20-40% of control values indicating a Mendelian mode of inheritance of the binding defect. In contrast, insulin stimulated autophosphorylation of the [~-chain of the insulin receptor shows normal values, indicating compensation mechanisms operating on this process. The stimulation of the basal level of 2-deoxyglucose uptake by insulin in fibroblasts from the homozygous patient is 1.2 fold whereas the heterozygous and control individuals show stimulation values of approximately 1.65 ff)ld. Basal levels of 2-deoxyglucose uptake are similar in these fibroblasts. Oral glucose tolerance tests on the heterozygous individuals indicate an increased requirement for insulin of the target tissues as concluded from the tendency towards hyperinsulinaemia with no observed hyperglycaemia. The results show that individuals with a genetic lesion in the insulin receptor which leads to decreased insulin binding, have mild abnormalities in their glucose tolerance tests but do not seem to develop hyperglycaemia as seen in Type 2 (non-insulin-dependent) diabetes mellitus.Key words: Leprechaunism, insulin receptor, insulin resistance, autophosphorylation, insulin binding, glucose tolerance tests.A variety of genetic defects may result in an impaired glucose homeostasis due to insulin resistance of the target tissues for insulin such as the liver, muscle and adipose tissue. The inherited syndromes of acanthosis nigricans type A and leprechaunism, which are characterized by an extreme resistance to insulin, are the result of mutations in the gene for the insulin receptor as indicated by recent data on molecular cloning of the insulin receptor DNA from these patients [1,2]. Type 2 (non-insulin-dependent) diabetes mellitus, being a disease with a strong genetic component, is also characterized by insulin resistance of the target tissues. The genetic components involved in the predisposition to Type 2 diabetes are unknown and it seems possible that the disease is polygenic in nature, complicating the identification of the genes involved in the pathogenesis of the disease.To investigate the effect of lesions in the insulin receptor gene on glucose homeostasis, we have examined insulin receptor functions and glucose tolerance in relatives from a leprechaun patient. This lep...

Mutant insulin receptors in syndromes of insulin resistance

“…Family studies showed that heterozygous relatives have modest to marked insulin resistance without any definite clinical phenotype (Lekanne-Deprez et al, 1989). In-vitro study of the expressed mutant receptor shows that the mutation inhibits cleavage and transport of the pro-receptor to thecell-surface.…”

“…Leprechaun Geldermalsen is the offspring of a consanguineous marriage and is homozygous for a Leu-+Pro mutation at codon 233 in the a-subunit (Klinkhamer et al, 1990). Family studies showed that heterozygous relatives have modest to marked insulin resistance without any definite clinical phenotype (Lekanne-Deprez et al, 1989). In-vitro study of the expressed mutant receptor shows that the mutation inhibits cleavage and transport of the pro-receptor to thecell-surface.…”

Insulin receptor and insulin-responsive glucose transporter (GLUT 4) mutations and polymorphisms in a welsh type 2 (non-insulin-dependent) diabetic population

“…In certain cases heterozygous relatives of such patients have had no obvious clinical features except moderate to marked h}~erinsulinaemia and sometimes, impairment of glucose tolerance [2]. This has led to increased interest in the possibility that a certain proportion of subjects with "typical" Type 2 (non-insulin-dependent) diabetes mellitus may harbour such mutations and that these might contribute to the inherited insulin resistance component of the disease.…”

A leucine-to-proline mutation in the insulin receptor in a family with insulin resistance.

“…The underlying molecular mechanism is not clear, although recent findings suggest the involvement of the insulin receptor (Kadowaki et al, 1988;Yoshimasa et al, 1988 (Lekanne Deprez et al, 1989). Cloning and sequencing of the patient's insulin receptor cDNA revealed a leucine-to-proline mutation at position 233 in the ca subunit.…”